bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–04–30
76 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Dangerous liaisons.
  2. Zoonomia.
  3. Sensing DCs.
  4. Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria.
  5. Primary vaccination imprint.
  6. A tubule-sheet continuum model for the mechanism of nuclear envelope assembly.
  7. Transcription factor binding site orientation and order are major drivers of gene regulatory activity.
  8. Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models.
  9. CAND1 orchestrates CRLs through rock and roll.
  10. Single duplex DNA sequencing with CODEC detects mutations with high sensitivity.
  11. Biological age is increased by stress and restored upon recovery.
  12. Sexual identity of enterocytes regulates autophagy to determine intestinal health, lifespan and responses to rapamycin.
  13. Copper catalyses changes in cell state.
  14. Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases.
  15. Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis.
  16. Seeing humans through an evolutionary lens.
  17. Resilient brains run out of (c)GAS.
  18. Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain.
  19. Alzheimer's disease modification mediated by bone marrow-derived macrophages via a TREM2-independent pathway in mouse model of amyloidosis.
  20. Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types.
  21. Csx28 is a membrane pore that enhances CRISPR-Cas13b-dependent antiphage defense.
  22. Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis.
  23. Cross-modal autoencoder framework learns holistic representations of cardiovascular state.
  24. Characterizing expression changes in noncoding RNAs during aging and heterochronic parabiosis across mouse tissues.
  25. Mammalian evolution of human cis-regulatory elements and transcription factor binding sites.
  26. Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity.
  27. Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals.
  28. Stomach-derived human insulin-secreting organoids restore glucose homeostasis.
  29. The functional and evolutionary impacts of human-specific deletions in conserved elements.
  30. Nuclear remodeling drives age-related cardiac dysfunction.
  31. Suppression of intestinal dysfunction in a Drosophila model of Parkinson's disease is neuroprotective.
  32. Direct determination of oligomeric organization of integral membrane proteins and lipids from intact customizable bilayer.
  33. Alternative splicing of GSDMB modulates killer lymphocyte-triggered pyroptosis.
  34. Ethical considerations for researchers developing and testing minimal-risk devices.
  35. MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca2+ uniporter channel.
  36. Cryptochrome-Timeless structure reveals circadian clock timing mechanisms.
  37. Charting granulopoietic disturbances in sepsis.
  38. Germinal centers FAMished without TFAM.
  39. IS21 family transposase cleaved donor complex traps two right-handed superhelical crossings.
  40. Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice.
  41. Spatiotemporal and global profiling of DNA-protein interactions enables discovery of low-affinity transcription factors.
  42. How flies remember a rich experience from its individual components.
  43. Impaired dynamics of precapillary sphincters and pericytes at first-order capillaries predict reduced neurovascular function in the aging mouse brain.
  44. Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F.
  45. Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma.
  46. Efficient engineering of human and mouse primary cells using peptide-assisted genome editing.
  47. USP7 controls NGN3 stability and pancreatic endocrine lineage development.
  48. Mesolimbic dopamine release precedes actively sought aversive stimuli in mice.
  49. Revealing concealed cardioprotection by platelet Mfsd2b-released S1P in human and murine myocardial infarction.
  50. Single-cell profiling of immune system alterations in lymphoid, barrier and solid tissues in aged mice.
  51. Complex topology meets simple statistics.
  52. Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production.
  53. Nuclear morphology is a deep learning biomarker of cellular senescence.
  54. Associations between in vitro, in vivo and in silico cell classes in mouse primary visual cortex.
  55. Inference of age-associated transcription factor regulatory activity changes in single cells.
  56. Aging-associated lncRNAs are evolutionarily conserved and participate in NFκB signaling.
  57. Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L.
  58. Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging.
  59. A hyper-quiescent chromatin state formed during aging is reversed by regeneration.
  60. A druggable copper-signalling pathway that drives inflammation.
  61. Photoselective sequencing: microscopically guided genomic measurements with subcellular resolution.
  62. HMGN1 enhances CRISPR-directed dual-function A-to-G and C-to-G base editing.
  63. Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.
  64. DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice.
  65. In vivo bioluminescence imaging of natural bacteria within deep tissues via ATP-binding cassette sugar transporter.
  66. Pleiotropic effects of mitochondria in aging.
  67. In vivo cyclic induction of the FOXM1 transcription factor delays natural and progeroid aging phenotypes and extends healthspan.
  68. RNA-mediated demixing transition of low-density condensates.
  69. Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia.
  70. Activation of innate immune cGAS-STING pathway contributes to Alzheimer's pathogenesis in 5×FAD mice.
  71. Age-related liver endothelial zonation triggers steatohepatitis by inactivating pericentral endothelium-derived C-kit.
  72. The transcriptional and regulatory identity of erythropoietin producing cells.
  73. CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.
  74. Rare genetic coding variants associated with human longevity and protection against age-related diseases.
  75. Skeletal muscle mitochondrial interactome remodeling is linked to functional decline in aged female mice.
  76. Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation.
  1. Nat Immunol. 2023 Apr 24.
    Dangerous liaisons.
    Laurie Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-023-01511-3
  2. Science. 2023 Apr 28. 380(6643): 356-357
    Zoonomia.
    Sacha Vignieri.
      
    DOI:  https://doi.org/10.1126/science.adi1599
  3. Nat Immunol. 2023 Apr 24.
    Sensing DCs.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-023-01514-0
  4. Nat Commun. 2023 Apr 24. 14(1): 2356
    Mitochondrial complex III deficiency drives c-MYC overexpression and illicit cell cycle entry leading to senescence and segmental progeria.
    Janne Purhonen, Rishi Banerjee, Vilma Wanne, Nina Sipari, Matthias Mörgelin, Vineta Fellman, Jukka Kallijärvi.
      Accumulating evidence suggests mitochondria as key modulators of normal and premature aging, yet whether primary oxidative phosphorylation (OXPHOS) deficiency can cause progeroid disease remains unclear. Here, we show that mice with severe isolated respiratory complex III (CIII) deficiency display nuclear DNA damage, cell cycle arrest, aberrant mitoses, and cellular senescence in the affected organs such as liver and kidney, and a systemic phenotype resembling juvenile-onset progeroid syndromes. Mechanistically, CIII deficiency triggers presymptomatic cancer-like c-MYC upregulation followed by excessive anabolic metabolism and illicit cell proliferation against lack of energy and biosynthetic precursors. Transgenic alternative oxidase dampens mitochondrial integrated stress response and the c-MYC induction, suppresses the illicit proliferation, and prevents juvenile lethality despite that canonical OXPHOS-linked functions remain uncorrected. Inhibition of c-MYC with the dominant-negative Omomyc protein relieves the DNA damage in CIII-deficient hepatocytes in vivo. Our results connect primary OXPHOS deficiency to genomic instability and progeroid pathogenesis and suggest that targeting c-MYC and aberrant cell proliferation may be therapeutic in mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-023-38027-1
  5. Nat Immunol. 2023 Apr 24.
    Primary vaccination imprint.
    Ioana Visan.
      
    DOI:  https://doi.org/10.1038/s41590-023-01515-z
  6. Dev Cell. 2023 Apr 24. pii: S1534-5807(23)00156-9. [Epub ahead of print]
    A tubule-sheet continuum model for the mechanism of nuclear envelope assembly.
    Gengjing Zhao, Shiwei Liu, Sanjana Arun, Fioranna Renda, Alexey Khodjakov, David Pellman.
      Nuclear envelope (NE) assembly defects cause chromosome fragmentation, cancer, and aging. However, major questions about the mechanism of NE assembly and its relationship to nuclear pathology are unresolved. In particular, how cells efficiently assemble the NE starting from vastly different, cell type-specific endoplasmic reticulum (ER) morphologies is unclear. Here, we identify a NE assembly mechanism, "membrane infiltration," that defines one end of a continuum with another NE assembly mechanism, "lateral sheet expansion," in human cells. Membrane infiltration involves the recruitment of ER tubules or small sheets to the chromatin surface by mitotic actin filaments. Lateral sheet expansion involves actin-independent envelopment of peripheral chromatin by large ER sheets that then extend over chromatin within the spindle. We propose a "tubule-sheet continuum" model that explains the efficient NE assembly from any starting ER morphology, the cell type-specific patterns of nuclear pore complex (NPC) assembly, and the obligatory NPC assembly defect of micronuclei.
    Keywords:  endoplasmic reticulum; micronuclei; mitosis; mitotic actin; myosin V; nuclear envelope; nuclear pore complexes
    DOI:  https://doi.org/10.1016/j.devcel.2023.04.003
  7. Nat Commun. 2023 Apr 22. 14(1): 2333
    Transcription factor binding site orientation and order are major drivers of gene regulatory activity.
    Ilias Georgakopoulos-Soares, Chengyu Deng, Vikram Agarwal, Candace S Y Chan, Jingjing Zhao, Fumitaka Inoue, Nadav Ahituv.
      The gene regulatory code and grammar remain largely unknown, precluding our ability to link phenotype to genotype in regulatory sequences. Here, using a massively parallel reporter assay (MPRA) of 209,440 sequences, we examine all possible pair and triplet combinations, permutations and orientations of eighteen liver-associated transcription factor binding sites (TFBS). We find that TFBS orientation and order have a major effect on gene regulatory activity. Corroborating these results with genomic analyses, we find clear human promoter TFBS orientation biases and similar TFBS orientation and order transcriptional effects in an MPRA that tested 164,307 liver candidate regulatory elements. Additionally, by adding TFBS orientation to a model that predicts expression from sequence we improve performance by 7.7%. Collectively, our results show that TFBS orientation and order have a significant effect on gene regulatory activity and need to be considered when analyzing the functional effect of variants on the activity of these sequences.
    DOI:  https://doi.org/10.1038/s41467-023-37960-5
  8. Nat Aging. 2022 Sep;2(9): 837-850
    Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models.
    Borislav Dejanovic, Tiffany Wu, Ming-Chi Tsai, David Graykowski, Vineela D Gandham, Christopher M Rose, Corey E Bakalarski, Hai Ngu, Yuanyuan Wang, Shristi Pandey, Mitchell G Rezzonico, Brad A Friedman, Rose Edmonds, Ann De Mazière, Raphael Rakosi-Schmidt, Tarjinder Singh, Judith Klumperman, Oded Foreman, Michael C Chang, Luke Xie, Morgan Sheng, Jesse E Hanson.
      Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in TauP301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in TauP301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in TauP301S mice and rescued synapse density. Finally, in an AD mouse model that combines β-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.
    DOI:  https://doi.org/10.1038/s43587-022-00281-1
  9. Cell. 2023 Apr 27. pii: S0092-8674(23)00372-0. [Epub ahead of print]186(9): 1817-1818
    CAND1 orchestrates CRLs through rock and roll.
    Yuan Xie, Minglei Zhao.
      Proper regulation of protein degradation is essential for cell physiology. In the current issue of Cell, Baek et al. elucidated how a large class of ubiquitin ligase, known as CRL, is assembled and disassembled through a key regulator, CAND1.
    DOI:  https://doi.org/10.1016/j.cell.2023.04.001
  10. Nat Genet. 2023 Apr 27.
    Single duplex DNA sequencing with CODEC detects mutations with high sensitivity.
    Jin H Bae, Ruolin Liu, Eugenia Roberts, Erica Nguyen, Shervin Tabrizi, Justin Rhoades, Timothy Blewett, Kan Xiong, Gregory Gydush, Douglas Shea, Zhenyi An, Sahil Patel, Ju Cheng, Sainetra Sridhar, Mei Hong Liu, Emilie Lassen, Anne-Bine Skytte, Marta Grońska-Pęski, Jonathan E Shoag, Gilad D Evrony, Heather A Parsons, Erica L Mayer, G Mike Makrigiorgos, Todd R Golub, Viktor A Adalsteinsson.
      Detecting mutations from single DNA molecules is crucial in many fields but challenging. Next-generation sequencing (NGS) affords tremendous throughput but cannot directly sequence double-stranded DNA molecules ('single duplexes') to discern the true mutations on both strands. Here we present Concatenating Original Duplex for Error Correction (CODEC), which confers single duplex resolution to NGS. CODEC affords 1,000-fold higher accuracy than NGS, using up to 100-fold fewer reads than duplex sequencing. CODEC revealed mutation frequencies of 2.72 × 10-8 in sperm of a 39-year-old individual, and somatic mutations acquired with age in blood cells. CODEC detected genome-wide, clonal hematopoiesis mutations from single DNA molecules, single mutated duplexes from tumor genomes and liquid biopsies, microsatellite instability with 10-fold greater sensitivity and mutational signatures, and specific tumor mutations with up to 100-fold fewer reads. CODEC enables more precise genetic testing and reveals biologically significant mutations, which are commonly obscured by NGS errors.
    DOI:  https://doi.org/10.1038/s41588-023-01376-0
  11. Cell Metab. 2023 Apr 04. pii: S1550-4131(23)00093-1. [Epub ahead of print]
    Biological age is increased by stress and restored upon recovery.
    Jesse R Poganik, Bohan Zhang, Gurpreet S Baht, Alexander Tyshkovskiy, Amy Deik, Csaba Kerepesi, Sun Hee Yim, Ake T Lu, Amin Haghani, Tong Gong, Anna M Hedman, Ellika Andolf, Göran Pershagen, Catarina Almqvist, Clary B Clish, Steve Horvath, James P White, Vadim N Gladyshev.
      Aging is classically conceptualized as an ever-increasing trajectory of damage accumulation and loss of function, leading to increases in morbidity and mortality. However, recent in vitro studies have raised the possibility of age reversal. Here, we report that biological age is fluid and exhibits rapid changes in both directions. At epigenetic, transcriptomic, and metabolomic levels, we find that the biological age of young mice is increased by heterochronic parabiosis and restored following surgical detachment. We also identify transient changes in biological age during major surgery, pregnancy, and severe COVID-19 in humans and/or mice. Together, these data show that biological age undergoes a rapid increase in response to diverse forms of stress, which is reversed following recovery from stress. Our study uncovers a new layer of aging dynamics that should be considered in future studies. The elevation of biological age by stress may be a quantifiable and actionable target for future interventions.
    Keywords:  aging; biological age; dynamics; epigenetic aging clocks; recovery; stress
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.015
  12. Nat Aging. 2022 Dec;2(12): 1145-1158
    Sexual identity of enterocytes regulates autophagy to determine intestinal health, lifespan and responses to rapamycin.
    Jennifer C Regan, Yu-Xuan Lu, Enric Ureña, Ralf L Meilenbrock, James H Catterson, Disna Kißler, Jenny Fröhlich, Emilie Funk, Linda Partridge.
      Pharmacological attenuation of mTOR presents a promising route for delay of age-related disease. Here we show that treatment of Drosophila with the mTOR inhibitor rapamycin extends lifespan in females, but not in males. Female-specific, age-related gut pathology is markedly slowed by rapamycin treatment, mediated by increased autophagy. Treatment increases enterocyte autophagy in females, via the H3/H4 histone-Bchs axis, whereas males show high basal levels of enterocyte autophagy that are not increased by rapamycin feeding. Enterocyte sexual identity, determined by transformerFemale expression, dictates sexually dimorphic cell size, H3/H4-Bchs expression, basal rates of autophagy, fecundity, intestinal homeostasis and lifespan extension in response to rapamycin. Dimorphism in autophagy is conserved in mice, where intestine, brown adipose tissue and muscle exhibit sex differences in autophagy and response to rapamycin. This study highlights tissue sex as a determining factor in the regulation of metabolic processes by mTOR and the efficacy of mTOR-targeted, anti-aging drug treatments.
    DOI:  https://doi.org/10.1038/s43587-022-00308-7
  13. Nature. 2023 Apr 26.
    Copper catalyses changes in cell state.
      
    Keywords:  Cell biology; Immunology
    DOI:  https://doi.org/10.1038/d41586-023-01330-4
  14. Nat Commun. 2023 Apr 22. 14(1): 2330
    Computational design and molecular dynamics simulations suggest the mode of substrate binding in ceramide synthases.
    Iris D Zelnik, Beatriz Mestre, Jonathan J Weinstein, Tamir Dingjan, Stav Izrailov, Shifra Ben-Dor, Sarel J Fleishman, Anthony H Futerman.
      Until now, membrane-protein stabilization has relied on iterations of mutations and screening. We now validate a one-step algorithm, mPROSS, for stabilizing membrane proteins directly from an AlphaFold2 model structure. Applied to the lipid-generating enzyme, ceramide synthase, 37 designed mutations lead to a more stable form of human CerS2. Together with molecular dynamics simulations, we propose a pathway by which substrates might be delivered to the ceramide synthases.
    DOI:  https://doi.org/10.1038/s41467-023-38047-x
  15. Nat Immunol. 2023 Apr 24.
    Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis.
    Emergency Medicine Research Oxford (EMROx)
      Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b+ sepsis neutrophils inhibited proliferation and activation of CD4+ T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2+ immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection.
    DOI:  https://doi.org/10.1038/s41590-023-01490-5
  16. Science. 2023 Apr 28. 380(6643): 360-361
    Seeing humans through an evolutionary lens.
    Irene Gallego Romero.
      A collection of mammalian genomes provides insights into human biology and evolution.
    DOI:  https://doi.org/10.1126/science.adh0745
  17. Nat Immunol. 2023 Apr 24.
    Resilient brains run out of (c)GAS.
    Andrea Francesca M Salvador, Jonathan Kipnis.
      
    DOI:  https://doi.org/10.1038/s41590-023-01485-2
  18. Nat Aging. 2023 Jan;3(1): 121-137
    Cell-type-specific aging clocks to quantify aging and rejuvenation in neurogenic regions of the brain.
    Matthew T Buckley, Eric D Sun, Benson M George, Ling Liu, Nicholas Schaum, Lucy Xu, Jaime M Reyes, Margaret A Goodell, Irving L Weissman, Tony Wyss-Coray, Thomas A Rando, Anne Brunet.
      The diversity of cell types is a challenge for quantifying aging and its reversal. Here we develop 'aging clocks' based on single-cell transcriptomics to characterize cell-type-specific aging and rejuvenation. We generated single-cell transcriptomes from the subventricular zone neurogenic region of 28 mice, tiling ages from young to old. We trained single-cell-based regression models to predict chronological age and biological age (neural stem cell proliferation capacity). These aging clocks are generalizable to independent cohorts of mice, other regions of the brains, and other species. To determine if these aging clocks could quantify transcriptomic rejuvenation, we generated single-cell transcriptomic datasets of neurogenic regions for two interventions-heterochronic parabiosis and exercise. Aging clocks revealed that heterochronic parabiosis and exercise reverse transcriptomic aging in neurogenic regions, but in different ways. This study represents the first development of high-resolution aging clocks from single-cell transcriptomic data and demonstrates their application to quantify transcriptomic rejuvenation.
    DOI:  https://doi.org/10.1038/s43587-022-00335-4
  19. Nat Aging. 2022 Jan;2(1): 60-73
    Alzheimer's disease modification mediated by bone marrow-derived macrophages via a TREM2-independent pathway in mouse model of amyloidosis.
    Raz Dvir-Szternfeld, Giulia Castellani, Michal Arad, Liora Cahalon, Sarah Phoebeluc Colaiuta, Hadas Keren-Shaul, Tommaso Croese, Chiara Burgaletto, Kuti Baruch, Tyler Ulland, Marco Colonna, Assaf Weiner, Ido Amit, Michal Schwartz.
      Microglia and monocyte-derived macrophages (MDM) are key players in dealing with Alzheimer's disease. In amyloidosis mouse models, activation of microglia was found to be TREM2 dependent. Here, using Trem2-/-5xFAD mice, we assessed whether MDM act via a TREM2-dependent pathway. We adopted a treatment protocol targeting the programmed cell death ligand-1 (PD-L1) immune checkpoint, previously shown to modify Alzheimer's disease via MDM involvement. Blockade of PD-L1 in Trem2-/-5xFAD mice resulted in cognitive improvement and reduced levels of water-soluble amyloid beta1-42 with no effect on amyloid plaque burden. Single-cell RNA sequencing revealed that MDM, derived from both Trem2-/- and Trem2+/+5xFAD mouse brains, express a unique set of genes encoding scavenger receptors (for example, Mrc1, Msr1). Blockade of monocyte trafficking using anti-CCR2 antibody completely abrogated the cognitive improvement induced by anti-PD-L1 treatment in Trem2-/-5xFAD mice and similarly, but to a lesser extent, in Trem2+/+5xFAD mice. These results highlight a TREM2-independent, disease-modifying activity of MDM in an amyloidosis mouse model.
    DOI:  https://doi.org/10.1038/s43587-021-00149-w
  20. Nat Aging. 2023 Mar;3(3): 327-345
    Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types.
    Methodios Ximerakis, Kristina M Holton, Richard M Giadone, Ceren Ozek, Monika Saxena, Samara Santiago, Xian Adiconis, Danielle Dionne, Lan Nguyen, Kavya M Shah, Jill M Goldstein, Caterina Gasperini, Ioannis A Gampierakis, Scott L Lipnick, Sean K Simmons, Sean M Buchanan, Amy J Wagers, Aviv Regev, Joshua Z Levin, Lee L Rubin.
      Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains after parabiosis. For each cell type, we cataloged alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions and senescence status. Our analyses identified gene signatures, demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest new strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.
    DOI:  https://doi.org/10.1038/s43587-023-00373-6
  21. Science. 2023 Apr 28. 380(6643): 410-415
    Csx28 is a membrane pore that enhances CRISPR-Cas13b-dependent antiphage defense.
    Arica R VanderWal, Jung-Un Park, Bogdan Polevoda, Julia K Nicosia, Adrian M Molina Vargas, Elizabeth H Kellogg, Mitchell R O'Connell.
      Type VI CRISPR-Cas systems use RNA-guided ribonuclease (RNase) Cas13 to defend bacteria against viruses, and some of these systems encode putative membrane proteins that have unclear roles in Cas13-mediated defense. We show that Csx28, of type VI-B2 systems, is a transmembrane protein that assists to slow cellular metabolism upon viral infection, increasing antiviral defense. High-resolution cryo-electron microscopy reveals that Csx28 forms an octameric pore-like structure. These Csx28 pores localize to the inner membrane in vivo. Csx28's antiviral activity in vivo requires sequence-specific cleavage of viral messenger RNAs by Cas13b, which subsequently results in membrane depolarization, slowed metabolism, and inhibition of sustained viral infection. Our work suggests a mechanism by which Csx28 acts as a downstream, Cas13b-dependent effector protein that uses membrane perturbation as an antiviral defense strategy.
    DOI:  https://doi.org/10.1126/science.abm1184
  22. Nat Immunol. 2023 Apr 24.
    Dynamic mitochondrial transcription and translation in B cells control germinal center entry and lymphomagenesis.
    Yavuz F Yazicioglu, Eros Marin, Ciaran Sandhu, Silvia Galiani, Iwan G A Raza, Mohammad Ali, Barbara Kronsteiner, Ewoud B Compeer, Moustafa Attar, Susanna J Dunachie, Michael L Dustin, Alexander J Clarke.
      Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.
    DOI:  https://doi.org/10.1038/s41590-023-01484-3
  23. Nat Commun. 2023 Apr 28. 14(1): 2436
    Cross-modal autoencoder framework learns holistic representations of cardiovascular state.
    Adityanarayanan Radhakrishnan, Sam F Friedman, Shaan Khurshid, Kenney Ng, Puneet Batra, Steven A Lubitz, Anthony A Philippakis, Caroline Uhler.
      A fundamental challenge in diagnostics is integrating multiple modalities to develop a joint characterization of physiological state. Using the heart as a model system, we develop a cross-modal autoencoder framework for integrating distinct data modalities and constructing a holistic representation of cardiovascular state. In particular, we use our framework to construct such cross-modal representations from cardiac magnetic resonance images (MRIs), containing structural information, and electrocardiograms (ECGs), containing myoelectric information. We leverage the learned cross-modal representation to (1) improve phenotype prediction from a single, accessible phenotype such as ECGs; (2) enable imputation of hard-to-acquire cardiac MRIs from easy-to-acquire ECGs; and (3) develop a framework for performing genome-wide association studies in an unsupervised manner. Our results systematically integrate distinct diagnostic modalities into a common representation that better characterizes physiologic state.
    DOI:  https://doi.org/10.1038/s41467-023-38125-0
  24. Nat Biotechnol. 2023 Apr 27.
    Characterizing expression changes in noncoding RNAs during aging and heterochronic parabiosis across mouse tissues.
    Viktoria Wagner, Fabian Kern, Oliver Hahn, Nicholas Schaum, Nicole Ludwig, Tobias Fehlmann, Annika Engel, Dominic Henn, Shusruto Rishik, Alina Isakova, Michelle Tan, Rene Sit, Norma Neff, Martin Hart, Eckart Meese, Steve Quake, Tony Wyss-Coray, Andreas Keller.
      Molecular mechanisms of organismal and cell aging remain incompletely understood. We, therefore, generated a body-wide map of noncoding RNA (ncRNA) expression in aging (16 organs at ten timepoints from 1 to 27 months) and rejuvenated mice. We found molecular aging trajectories are largely tissue-specific except for eight broadly deregulated microRNAs (miRNAs). Their individual abundance mirrors their presence in circulating plasma and extracellular vesicles (EVs) whereas tissue-specific ncRNAs were less present. For miR-29c-3p, we observe the largest correlation with aging in solid organs, plasma and EVs. In mice rejuvenated by heterochronic parabiosis, miR-29c-3p was the most prominent miRNA restored to similar levels found in young liver. miR-29c-3p targets the extracellular matrix and secretion pathways, known to be implicated in aging. We provide a map of organism-wide expression of ncRNAs with aging and rejuvenation and identify a set of broadly deregulated miRNAs, which may function as systemic regulators of aging via plasma and EVs.
    DOI:  https://doi.org/10.1038/s41587-023-01751-6
  25. Science. 2023 Apr 28. 380(6643): eabn7930
    Mammalian evolution of human cis-regulatory elements and transcription factor binding sites.
    Zoonomia Consortium§
      Understanding the regulatory landscape of the human genome is a long-standing objective of modern biology. Using the reference-free alignment across 241 mammalian genomes produced by the Zoonomia Consortium, we charted evolutionary trajectories for 0.92 million human candidate cis-regulatory elements (cCREs) and 15.6 million human transcription factor binding sites (TFBSs). We identified 439,461 cCREs and 2,024,062 TFBSs under evolutionary constraint. Genes near constrained elements perform fundamental cellular processes, whereas genes near primate-specific elements are involved in environmental interaction, including odor perception and immune response. About 20% of TFBSs are transposable element-derived and exhibit intricate patterns of gains and losses during primate evolution whereas sequence variants associated with complex traits are enriched in constrained TFBSs. Our annotations illuminate the regulatory functions of the human genome.
    DOI:  https://doi.org/10.1126/science.abn7930
  26. Nat Aging. 2022 Sep;2(9): 796-808
    Decreased spliceosome fidelity and egl-8 intron retention inhibit mTORC1 signaling to promote longevity.
    Wenming Huang, Chun Kew, Stephanie de Alcantara Fernandes, Anna Löhrke, Lynn Han, Constantinos Demetriades, Adam Antebi.
      Changes in splicing fidelity are associated with loss of homeostasis and aging, yet only a handful of splicing factors have been shown to be causally required to promote longevity, and the underlying mechanisms and downstream targets in these paradigms remain elusive. Surprisingly, we found a hypomorphic mutation within ribonucleoprotein RNP-6/poly(U)-binding factor 60 kDa (PUF60), a spliceosome component promoting weak 3'-splice site recognition, which causes aberrant splicing, elevates stress responses and enhances longevity in Caenorhabditis elegans. Through genetic suppressor screens, we identify a gain-of-function mutation within rbm-39, an RNP-6-interacting splicing factor, which increases nuclear speckle formation, alleviates splicing defects and curtails longevity caused by rnp-6 mutation. By leveraging the splicing changes induced by RNP-6/RBM-39 activities, we uncover intron retention in egl-8/phospholipase C β4 (PLCB4) as a key splicing target prolonging life. Genetic and biochemical evidence show that neuronal RNP-6/EGL-8 downregulates mammalian target of rapamycin complex 1 (mTORC1) signaling to control organismal lifespan. In mammalian cells, PUF60 downregulation also potently and specifically inhibits mTORC1 signaling. Altogether, our results reveal that splicing fidelity modulates lifespan through mTOR signaling.
    DOI:  https://doi.org/10.1038/s43587-022-00275-z
  27. Cell Metab. 2023 Apr 20. pii: S1550-4131(23)00130-4. [Epub ahead of print]
    Integrative genetic analysis identifies FLVCR1 as a plasma-membrane choline transporter in mammals.
    Timothy C Kenny, Artem Khan, Yeeun Son, Lishu Yue, Søren Heissel, Anurag Sharma, H Amalia Pasolli, Yuyang Liu, Eric R Gamazon, Hanan Alwaseem, Richard K Hite, Kıvanç Birsoy.
      Genome-wide association studies (GWASs) of serum metabolites have the potential to uncover genes that influence human metabolism. Here, we combined an integrative genetic analysis that associates serum metabolites to membrane transporters with a coessentiality map of metabolic genes. This analysis revealed a connection between feline leukemia virus subgroup C cellular receptor 1 (FLVCR1) and phosphocholine, a downstream metabolite of choline metabolism. Loss of FLVCR1 in human cells strongly impairs choline metabolism due to the inhibition of choline import. Consistently, CRISPR-based genetic screens identified phospholipid synthesis and salvage machinery as synthetic lethal with FLVCR1 loss. Cells and mice lacking FLVCR1 exhibit structural defects in mitochondria and upregulate integrated stress response (ISR) through heme-regulated inhibitor (HRI) kinase. Finally, Flvcr1 knockout mice are embryonic lethal, which is partially rescued by choline supplementation. Altogether, our findings propose FLVCR1 as a major choline transporter in mammals and provide a platform to discover substrates for unknown metabolite transporters.
    Keywords:  FLVCR1; PCARP; choline; metabolism; mitochondria; phosphatidylcholine
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.003
  28. Nat Cell Biol. 2023 Apr 27.
    Stomach-derived human insulin-secreting organoids restore glucose homeostasis.
    Xiaofeng Huang, Wei Gu, Jiaoyue Zhang, Ying Lan, Jonathan L Colarusso, Sanlan Li, Christoph Pertl, Jiaqi Lu, Hyunkee Kim, Jian Zhu, David T Breault, Jean Sévigny, Qiao Zhou.
      Gut stem cells are accessible by biopsy and propagate robustly in culture, offering an invaluable resource for autologous cell therapies. Insulin-producing cells can be induced in mouse gut, but it has not been possible to generate abundant and durable insulin-secreting cells from human gut tissues to evaluate their potential as a cell therapy for diabetes. Here we describe a protocol to differentiate cultured human gastric stem cells into pancreatic islet-like organoids containing gastric insulin-secreting (GINS) cells that resemble β-cells in molecular hallmarks and function. Sequential activation of the inducing factors NGN3 and PDX1-MAFA led human gastric stem cells onto a distinctive differentiation path, including a SOX4High endocrine and GalaninHigh GINS precursor, before adopting β-cell identity, at efficiencies close to 70%. GINS organoids acquired glucose-stimulated insulin secretion in 10 days and restored glucose homeostasis for over 100 days in diabetic mice after transplantation, providing proof of concept for a promising approach to treat diabetes.
    DOI:  https://doi.org/10.1038/s41556-023-01130-y
  29. Science. 2023 Apr 28. 380(6643): eabn2253
    The functional and evolutionary impacts of human-specific deletions in conserved elements.
    Zoonomia Consortium†
      Conserved genomic sequences disrupted in humans may underlie uniquely human phenotypic traits. We identified and characterized 10,032 human-specific conserved deletions (hCONDELs). These short (average 2.56 base pairs) deletions are enriched for human brain functions across genetic, epigenomic, and transcriptomic datasets. Using massively parallel reporter assays in six cell types, we discovered 800 hCONDELs conferring significant differences in regulatory activity, half of which enhance rather than disrupt regulatory function. We highlight several hCONDELs with putative human-specific effects on brain development, including HDAC5, CPEB4, and PPP2CA. Reverting an hCONDEL to the ancestral sequence alters the expression of LOXL2 and developmental genes involved in myelination and synaptic function. Our data provide a rich resource to investigate the evolutionary mechanisms driving new traits in humans and other species.
    DOI:  https://doi.org/10.1126/science.abn2253
  30. Nat Aging. 2023 Jan;3(1): 15-16
    Nuclear remodeling drives age-related cardiac dysfunction.
      
    DOI:  https://doi.org/10.1038/s43587-022-00324-7
  31. Nat Aging. 2022 Apr;2(4): 317-331
    Suppression of intestinal dysfunction in a Drosophila model of Parkinson's disease is neuroprotective.
    Giorgio Fedele, Samantha H Y Loh, Ivana Celardo, Nuno Santos Leal, Susann Lehmann, Ana C Costa, L Miguel Martins.
      The innate immune response mounts a defense against foreign invaders and declines with age. An inappropriate induction of this response can cause diseases. Previous studies showed that mitochondria can be repurposed to promote inflammatory signaling. Damaged mitochondria can also trigger inflammation and promote diseases. Mutations in pink1, a gene required for mitochondrial health, cause Parkinson's disease, and Drosophila melanogaster pink1 mutants accumulate damaged mitochondria. Here, we show that defective mitochondria in pink1 mutants activate Relish targets and demonstrate that inflammatory signaling causes age-dependent intestinal dysfunction in pink1-mutant flies. These effects result in the death of intestinal cells, metabolic reprogramming and neurotoxicity. We found that Relish signaling is activated downstream of a pathway stimulated by cytosolic DNA. Suppression of Relish in the intestinal midgut of pink1-mutant flies restores mitochondrial function and is neuroprotective. We thus conclude that gut-brain communication modulates neurotoxicity in a fly model of Parkinson's disease through a mechanism involving mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s43587-022-00194-z
  32. Nat Methods. 2023 Apr 27.
    Direct determination of oligomeric organization of integral membrane proteins and lipids from intact customizable bilayer.
    Aniruddha Panda, Fabian Giska, Anna L Duncan, Alexander J Welch, Caroline Brown, Rachel McAllister, Parameswaran Hariharan, Jean N D Goder, Jeff Coleman, Sathish Ramakrishnan, Frédéric Pincet, Lan Guan, Shyam Krishnakumar, James E Rothman, Kallol Gupta.
      Hierarchical organization of integral membrane proteins (IMP) and lipids at the membrane is essential for regulating myriad downstream signaling. A quantitative understanding of these processes requires both detections of oligomeric organization of IMPs and lipids directly from intact membranes and determination of key membrane components and properties that regulate them. Addressing this, we have developed a platform that enables native mass spectrometry (nMS) analysis of IMP-lipid complexes directly from intact and customizable lipid membranes. Both the lipid composition and membrane properties (such as curvature, tension, and fluidity) of these bilayers can be precisely customized to a target membrane. Subsequent direct nMS analysis of these intact proteolipid vesicles can yield the oligomeric states of the embedded IMPs, identify bound lipids, and determine the membrane properties that can regulate the observed IMP-lipid organization. Applying this method, we show how lipid binding regulates neurotransmitter release and how membrane composition regulates the functional oligomeric state of a transporter.
    DOI:  https://doi.org/10.1038/s41592-023-01864-5
  33. Sci Immunol. 2023 Apr 28. 8(82): eadg3196
    Alternative splicing of GSDMB modulates killer lymphocyte-triggered pyroptosis.
    Qing Kong, Shiyu Xia, Xingxin Pan, Kaixiong Ye, Zhouyihan Li, Haoyan Li, Xiaoqiang Tang, Nidhi Sahni, S Stephen Yi, Xing Liu, Hao Wu, Michael B Elowitz, Judy Lieberman, Zhibin Zhang.
      Granzyme A from killer lymphocytes cleaves gasdermin B (GSDMB) and triggers pyroptosis in targeted human tumor cells, eliciting antitumor immunity. However, GSDMB has a controversial role in pyroptosis and has been linked to both anti- and protumor functions. Here, we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of GSDMB isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2, and 5 did not. The nonfunctional isoforms have a deleted or modified exon 6 and therefore lack a stable belt motif. The belt likely contributes to the insertion of oligomeric GSDMB-NTs into the membrane. Consistently, noncytotoxic GSDMB-NTs blocked pyroptosis caused by cytotoxic GSDMB-NTs in a dominant-negative manner. Upon natural killer (NK) cell attack, GSDMB3-expressing cells died by pyroptosis, whereas GSDMB4-expressing cells died by mixed pyroptosis and apoptosis, and GSDMB1/2-expressing cells died only by apoptosis. GSDMB4 partially resisted NK cell-triggered cleavage, suggesting that only GSDMB3 is fully functional. GSDMB1-3 were the most abundant isoforms in the tested tumor cell lines and were similarly induced by interferon-γ and the chemotherapy drug methotrexate. Expression of cytotoxic GSDMB3/4 isoforms, but not GSDMB1/2 isoforms that are frequently up-regulated in tumors, was associated with better outcomes in bladder and cervical cancers, suggesting that GSDMB3/4-mediated pyroptosis was protective in those tumors. Our study indicates that tumors may block and evade killer cell-triggered pyroptosis by generating noncytotoxic GSDMB isoforms. Therefore, therapeutics that favor the production of cytotoxic GSDMB isoforms by alternative splicing may improve antitumor immunity.
    DOI:  https://doi.org/10.1126/sciimmunol.adg3196
  34. Nat Commun. 2023 Apr 22. 14(1): 2325
    Ethical considerations for researchers developing and testing minimal-risk devices.
    Anna Wexler, Emily Largent.
      
    DOI:  https://doi.org/10.1038/s41467-023-38068-6
  35. Sci Signal. 2023 04 25. 16(782): eabi8948
    MICU1 regulates mitochondrial cristae structure and function independently of the mitochondrial Ca2+ uniporter channel.
    Dhanendra Tomar, Manfred Thomas, Joanne F Garbincius, Devin W Kolmetzky, Oniel Salik, Pooja Jadiya, Suresh K Joseph, April C Carpenter, György Hajnóczky, John W Elrod.
      MICU1 is a calcium (Ca2+)-binding protein that regulates the mitochondrial Ca2+ uniporter channel complex (mtCU) and mitochondrial Ca2+ uptake. MICU1 knockout mice display disorganized mitochondrial architecture, a phenotype that is distinct from that of mice with deficiencies in other mtCU subunits and, thus, is likely not explained by changes in mitochondrial matrix Ca2+ content. Using proteomic and cellular imaging techniques, we found that MICU1 localized to the mitochondrial contact site and cristae organizing system (MICOS) and directly interacted with the MICOS components MIC60 and CHCHD2 independently of the mtCU. We demonstrated that MICU1 was essential for MICOS complex formation and that MICU1 ablation resulted in altered cristae organization, mitochondrial ultrastructure, mitochondrial membrane dynamics, and cell death signaling. Together, our results suggest that MICU1 is an intermembrane space Ca2+ sensor that modulates mitochondrial membrane dynamics independently of matrix Ca2+ uptake. This system enables distinct Ca2+ signaling in the mitochondrial matrix and at the intermembrane space to modulate cellular energetics and cell death in a concerted manner.
    DOI:  https://doi.org/10.1126/scisignal.abi8948
  36. Nature. 2023 Apr 26.
    Cryptochrome-Timeless structure reveals circadian clock timing mechanisms.
    Changfan Lin, Shi Feng, Cristina C DeOliveira, Brian R Crane.
      Circadian rhythms influence many behaviours and diseases1,2. They arise from oscillations in gene expression caused by repressor proteins that directly inhibit transcription of their own genes. The fly circadian clock offers a valuable model for studying these processes, wherein Timeless (Tim) plays a critical role in mediating nuclear entry of the transcriptional repressor Period (Per) and the photoreceptor Cryptochrome (Cry) entrains the clock by triggering Tim degradation in light2,3. Here, through cryogenic electron microscopy of the Cry-Tim complex, we show how a light-sensing cryptochrome recognizes its target. Cry engages a continuous core of amino-terminal Tim armadillo repeats, resembling how photolyases recognize damaged DNA, and binds a C-terminal Tim helix, reminiscent of the interactions between light-insensitive cryptochromes and their partners in mammals. The structure highlights how the Cry flavin cofactor undergoes conformational changes that couple to large-scale rearrangements at the molecular interface, and how a phosphorylated segment in Tim may impact clock period by regulating the binding of Importin-α and the nuclear import of Tim-Per4,5. Moreover, the structure reveals that the N terminus of Tim inserts into the restructured Cry pocket to replace the autoinhibitory C-terminal tail released by light, thereby providing a possible explanation for how the long-short Tim polymorphism adapts flies to different climates6,7.
    DOI:  https://doi.org/10.1038/s41586-023-06009-4
  37. Nat Immunol. 2023 Apr 24.
    Charting granulopoietic disturbances in sepsis.
    Roza Maria Barouni, Renato Ostuni.
      
    DOI:  https://doi.org/10.1038/s41590-023-01495-0
  38. Nat Immunol. 2023 Apr 27.
    Germinal centers FAMished without TFAM.
    Julia Jellusova.
      
    DOI:  https://doi.org/10.1038/s41590-023-01507-z
  39. Nat Commun. 2023 Apr 22. 14(1): 2335
    IS21 family transposase cleaved donor complex traps two right-handed superhelical crossings.
    Mercedes Spínola-Amilibia, Lidia Araújo-Bazán, Álvaro de la Gándara, James M Berger, Ernesto Arias-Palomo.
      Transposases are ubiquitous enzymes that catalyze DNA rearrangement events with broad impacts on gene expression, genome evolution, and the spread of drug-resistance in bacteria. Here, we use biochemical and structural approaches to define the molecular determinants by which IstA, a transposase present in the widespread IS21 family of mobile elements, catalyzes efficient DNA transposition. Solution studies show that IstA engages the transposon terminal sequences to form a high-molecular weight complex and promote DNA integration. A 3.4 Å resolution structure of the transposase bound to transposon ends corroborates our biochemical findings and reveals that IstA self-assembles into a highly intertwined tetramer that synapses two supercoiled terminal inverted repeats. The three-dimensional organization of the IstA•DNA cleaved donor complex reveals remarkable similarities with retroviral integrases and classic transposase systems, such as Tn7 and bacteriophage Mu, and provides insights into IS21 transposition.
    DOI:  https://doi.org/10.1038/s41467-023-38071-x
  40. Nat Aging. 2022 Nov;2(11): 1008-1023
    Epigenetic reversal of hematopoietic stem cell aging in Phf6-knockout mice.
    Agnieszka A Wendorff, S Aidan Quinn, Silvia Alvarez, Jessie A Brown, Mayukh Biswas, Thomas Gunning, Teresa Palomero, Adolfo A Ferrando.
      Aging is characterized by an accumulation of myeloid-biased hematopoietic stem cells (HSCs) with reduced developmental potential. Genotoxic stress and epigenetic alterations have been proposed to mediate age-related HSC loss of regenerative and self-renewal potential. However, the mechanisms underlying these changes remain largely unknown. Genetic inactivation of the plant homeodomain 6 (Phf6) gene, a nucleolar and chromatin-associated factor, antagonizes age-associated HSC decline. Immunophenotyping, single-cell transcriptomic analyses and transplantation assays demonstrated markedly decreased accumulation of immunophenotypically defined HSCs, reduced myeloid bias and increased hematopoietic reconstitution capacity with preservation of lymphoid differentiation potential in Phf6-knockout HSCs from old mice. Moreover, deletion of Phf6 in aged mice rejuvenated immunophenotypic, transcriptional and functional hallmarks of aged HSCs. Long-term HSCs from old Phf6-knockout mice showed epigenetic rewiring and transcriptional programs consistent with decreased genotoxic stress-induced HSC aging. These results identify Phf6 as an important epigenetic regulator of HSC aging.
    DOI:  https://doi.org/10.1038/s43587-022-00304-x
  41. Nat Chem. 2023 Apr 27.
    Spatiotemporal and global profiling of DNA-protein interactions enables discovery of low-affinity transcription factors.
    An-Di Guo, Ke-Nian Yan, Hao Hu, Linhui Zhai, Teng-Fei Hu, Haixia Su, Yijia Chi, Jinyin Zha, Yechun Xu, Dongxin Zhao, Xiaojie Lu, Yong-Jiang Xu, Jian Zhang, Minjia Tan, Xiao-Hua Chen.
      Precise dissection of DNA-protein interactions is essential for elucidating the recognition basis, dynamics and gene regulation mechanism. However, global profiling of weak and dynamic DNA-protein interactions remains a long-standing challenge. Here, we establish the light-induced lysine (K) enabled crosslinking (LIKE-XL) strategy for spatiotemporal and global profiling of DNA-protein interactions. Harnessing unique abilities to capture weak and transient DNA-protein interactions, we demonstrate that LIKE-XL enables the discovery of low-affinity transcription-factor/DNA interactions via sequence-specific DNA baits, determining the binding sites for transcription factors that have been previously unknown. More importantly, we successfully decipher the dynamics of the transcription factor subproteome in response to drug treatment in a time-resolved manner, and find downstream target transcription factors from drug perturbations, providing insight into their dynamic transcriptional networks. The LIKE-XL strategy offers a complementary method to expand the DNA-protein profiling toolbox and map accurate DNA-protein interactomes that were previously inaccessible via non-covalent strategies, for better understanding of protein function in health and disease.
    DOI:  https://doi.org/10.1038/s41557-023-01196-z
  42. Nature. 2023 Apr 26.
    How flies remember a rich experience from its individual components.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-01333-1
  43. Nat Aging. 2023 Feb;3(2): 173-184
    Impaired dynamics of precapillary sphincters and pericytes at first-order capillaries predict reduced neurovascular function in the aging mouse brain.
    Changsi Cai, Stefan Andreas Zambach, Søren Grubb, Lechan Tao, Chen He, Barbara Lykke Lind, Kirsten Joan Thomsen, Xiao Zhang, Bjørn Olav Hald, Reena Murmu Nielsen, Kayeon Kim, Anna Devor, Micael Lønstrup, Martin Johannes Lauritzen.
      The microvascular inflow tract, comprising the penetrating arterioles, precapillary sphincters and first-order capillaries, is the bottleneck for brain blood flow and energy supply. Exactly how aging alters the structure and function of the microvascular inflow tract remains unclear. By in vivo four-dimensional two-photon imaging, we reveal an age-dependent decrease in vaso-responsivity accompanied by a decrease in vessel density close to the arterioles and loss of vascular mural cell processes, although the number of mural cell somas and their alpha smooth muscle actin density were preserved. The age-related reduction in vascular reactivity was mostly pronounced at precapillary sphincters, highlighting their crucial role in capillary blood flow regulation. Mathematical modeling revealed impaired pressure and flow control in aged mice during vasoconstriction. Interventions that preserve dynamics of cerebral blood vessels may ameliorate age-related decreases in blood flow and prevent brain frailty.
    DOI:  https://doi.org/10.1038/s43587-022-00354-1
  44. Nat Commun. 2023 Apr 26. 14(1): 2400
    Mini-PCDH15 gene therapy rescues hearing in a mouse model of Usher syndrome type 1F.
    Maryna V Ivanchenko, Daniel M Hathaway, Alex J Klein, Bifeng Pan, Olga Strelkova, Pedro De-la-Torre, Xudong Wu, Cole W Peters, Eric M Mulhall, Kevin T Booth, Corey Goldstein, Joseph Brower, Marcos Sotomayor, Artur A Indzhykulian, David P Corey.
      Usher syndrome type 1 F (USH1F), caused by mutations in the protocadherin-15 gene (PCDH15), is characterized by congenital deafness, lack of balance, and progressive blindness. In hair cells, the receptor cells of the inner ear, PCDH15 is a component of tip links, fine filaments which pull open mechanosensory transduction channels. A simple gene addition therapy for USH1F is challenging because the PCDH15 coding sequence is too large for adeno-associated virus (AAV) vectors. We use rational, structure-based design to engineer mini-PCDH15s in which 3-5 of the 11 extracellular cadherin repeats are deleted, but which still bind a partner protein. Some mini-PCDH15s can fit in an AAV. An AAV encoding one of these, injected into the inner ears of mouse models of USH1F, produces a mini-PCDH15 which properly forms tip links, prevents the degeneration of hair cell bundles, and rescues hearing. Mini-PCDH15s may be a useful therapy for the deafness of USH1F.
    DOI:  https://doi.org/10.1038/s41467-023-38038-y
  45. J Clin Invest. 2023 May 01. pii: e164528. [Epub ahead of print]133(9):
    Targeting fibrinogen-like protein 1 enhances immunotherapy in hepatocellular carcinoma.
    Mingen Lin, Jing He, Xinchao Zhang, Xue Sun, Wenjing Dong, Ruonan Zhang, Yanping Xu, Lei Lv.
      How cancer cells evade the therapeutic effects of immune checkpoint blockade is largely unknown. Here, we report that fibrinogen-like protein 1 (FGL1), a newly identified immune checkpoint ligand, was modified by acetylation at Lys 98 in hepatocellular carcinoma (HCC), which targeted it for proteasomal degradation. Sirtuin 2 (SIRT2) deacetylated and stabilized FGL1, thus promoting immune evasion. Notably, the SIRT2 inhibitor 2-Cyano-3-[5-(2,5-dichlorophenyl)-2-furanyl]-N-5-quinolinyl-2-propenamide (AGK2) enhanced acetylation of FGL1 and reduced FGL1 protein levels in vitro. The combination of AGK2 and programmed death ligand 1 (PD-L1) blockade effectively suppressed tumor growth and improved overall survival of mice. Furthermore, aspirin, an old drug, could directly acetylate FGL1 at Lys 98 and promote its degradation in vitro. Aspirin enhanced the immunotherapeutic efficacy, induced tumor regression, and extended the lifespan of tumor-bearing mice. Furthermore, the SIRT2/FGL1 axis was expressed in HCC specimens. Collectively, these findings unveil an acetylation-mediated regulation of FGL1, identify a potential target for HCC immunotherapy, and provide therapeutic strategies for the clinical treatment of HCC.
    Keywords:  Cancer immunotherapy; Cell Biology; Immunology; Immunotherapy; Liver cancer
    DOI:  https://doi.org/10.1172/JCI164528
  46. Nat Biotechnol. 2023 Apr 24.
    Efficient engineering of human and mouse primary cells using peptide-assisted genome editing.
    Zhen Zhang, Amy E Baxter, Diqiu Ren, Kunhua Qin, Zeyu Chen, Sierra M Collins, Hua Huang, Chad A Komar, Peter F Bailer, Jared B Parker, Gerd A Blobel, Rahul M Kohli, E John Wherry, Shelley L Berger, Junwei Shi.
      Simple, efficient and well-tolerated delivery of CRISPR genome editing systems into primary cells remains a major challenge. Here we describe an engineered Peptide-Assisted Genome Editing (PAGE) CRISPR-Cas system for rapid and robust editing of primary cells with minimal toxicity. The PAGE system requires only a 30-min incubation with a cell-penetrating Cas9 or Cas12a and a cell-penetrating endosomal escape peptide to achieve robust single and multiplex genome editing. Unlike electroporation-based methods, PAGE gene editing has low cellular toxicity and shows no significant transcriptional perturbation. We demonstrate rapid and efficient editing of primary cells, including human and mouse T cells, as well as human hematopoietic progenitor cells, with editing efficiencies upwards of 98%. PAGE provides a broadly generalizable platform for next-generation genome engineering in primary cells.
    DOI:  https://doi.org/10.1038/s41587-023-01756-1
  47. Nat Commun. 2023 Apr 28. 14(1): 2457
    USP7 controls NGN3 stability and pancreatic endocrine lineage development.
    Teodora Manea, Jessica Kristine Nelson, Cristina Maria Garrone, Karin Hansson, Ian Evans, Axel Behrens, Rocio Sancho.
      Understanding the factors and mechanisms involved in beta-cell development will guide therapeutic efforts to generate fully functional beta cells for diabetes. Neurogenin 3 (NGN3) is the key transcription factor that marks endocrine progenitors and drives beta-cell differentiation. Here we screen for binding partners of NGN3 and identify the deubiquitylating enzyme USP7 as a key regulator of NGN3 stability. Mechanistically, USP7 interacts with, deubiquitinates and stabilizes NGN3. In vivo, conditional knockout of Usp7 in the mouse embryonic pancreas causes a dramatic reduction in islet formation and hyperglycemia in adult mice, due to impaired NGN3-mediated endocrine specification during pancreatic development. Furthermore, pharmacological inhibition of USP7 during endocrine specification in human iPSC models of beta-cell differentiation decreases NGN3 expressing progenitor cell numbers and impairs beta cell differentiation. Thus, the USP7-NGN3 axis is an essential mechanism for driving endocrine development and beta-cell differentiation, which can be therapeutically exploited.
    DOI:  https://doi.org/10.1038/s41467-023-38146-9
  48. Nat Commun. 2023 Apr 27. 14(1): 2433
    Mesolimbic dopamine release precedes actively sought aversive stimuli in mice.
    Yosuke Yawata, Yu Shikano, Jun Ogasawara, Kenichi Makino, Tetsuhiko Kashima, Keiko Ihara, Airi Yoshimoto, Shota Morikawa, Sho Yagishita, Kenji F Tanaka, Yuji Ikegaya.
      In some models, animals approach aversive stimuli more than those housed in an enriched environment. Here, we found that male mice in an impoverished and unstimulating (i.e., boring) chamber without toys sought aversive air puffs more often than those in an enriched chamber. Using this animal model, we identified the insular cortex as a regulator of aversion-seeking behavior. Activation and inhibition of the insular cortex increased and decreased the frequencies of air-puff self-stimulation, respectively, and the firing patterns of insular neuron ensembles predicted the self-stimulation timing. Dopamine levels in the ventrolateral striatum decreased with passive air puffs but increased with actively sought puffs. Around 20% of mice developed intense self-stimulation despite being offered toys, which was prevented by administering opioid receptor antagonists. This study establishes a basis for comprehending the neural underpinnings of usually avoided stimulus-seeking behaviors.
    DOI:  https://doi.org/10.1038/s41467-023-38130-3
  49. Nat Commun. 2023 Apr 26. 14(1): 2404
    Revealing concealed cardioprotection by platelet Mfsd2b-released S1P in human and murine myocardial infarction.
    Amin Polzin, Lisa Dannenberg, Marcel Benkhoff, Maike Barcik, Carolin Helten, Philipp Mourikis, Samantha Ahlbrecht, Laura Wildeis, Justus Ziese, Dorothee Zikeli, Daniel Metzen, Hao Hu, Leonard Baensch, Nathalie H Schröder, Petra Keul, Sarah Weske, Philipp Wollnitzke, Dragos Duse, Süreyya Saffak, Mareike Cramer, Florian Bönner, Tina Müller, Markus H Gräler, Tobias Zeus, Malte Kelm, Bodo Levkau.
      Antiplatelet medication is standard of care in acute myocardial infarction (AMI). However, it may have obscured beneficial properties of the activated platelet secretome. We identify platelets as major source of a sphingosine-1-phosphate (S1P) burst during AMI, and find its magnitude to favorably associate with cardiovascular mortality and infarct size in STEMI patients over 12 months. Experimentally, administration of supernatant from activated platelets reduces infarct size in murine AMI, which is blunted in platelets deficient for S1P export (Mfsd2b) or production (Sphk1) and in mice deficient for cardiomyocyte S1P receptor 1 (S1P1). Our study reveals an exploitable therapeutic window in antiplatelet therapy in AMI as the GPIIb/IIIa antagonist tirofiban preserves S1P release and cardioprotection, whereas the P2Y12 antagonist cangrelor does not. Here, we report that platelet-mediated intrinsic cardioprotection is an exciting therapeutic paradigm reaching beyond AMI, the benefits of which may need to be considered in all antiplatelet therapies.
    DOI:  https://doi.org/10.1038/s41467-023-38069-5
  50. Nat Aging. 2022 Jan;2(1): 74-89
    Single-cell profiling of immune system alterations in lymphoid, barrier and solid tissues in aged mice.
    Sinduya Krishnarajah, Florian Ingelfinger, Ekaterina Friebel, Dilay Cansever, Ana Amorim, Myrto Andreadou, David Bamert, Gioana Litscher, Mirjam Lutz, Maud Mayoux, Sarah Mundt, Frederike Ridder, Colin Sparano, Sebastian Anton Stifter, Can Ulutekin, Susanne Unger, Marijne Vermeer, Pascale Zwicky, Melanie Greter, Sonia Tugues, Donatella De Feo, Burkhard Becher.
      Aging exerts profound and paradoxical effects on the immune system, at once impairing proliferation, cytotoxicity and phagocytosis, and inducing chronic inflammation. Previous studies have focused on individual tissues or cell types, while a comprehensive multisystem study of tissue-resident and circulating immune populations during aging is lacking. Here we reveal an atlas of age-related changes in the abundance and phenotype of immune cell populations across 12 mouse tissues. Using cytometry-based high parametric analysis of 37 mass-cytometry and 55 spectral flow-cytometry parameters, mapping samples from young and aged animals revealed conserved and tissue-type-specific patterns of both immune atrophy and expansion. We uncovered clear phenotypic changes in both lymphoid and myeloid lineages in aged mice, and in particular a contraction in natural killer cells and plasmacytoid dendritic cells. These changes correlated with a skewing towards myelopoiesis at the expense of early lymphocyte genesis in aged mice. Taken together, this atlas represents a comprehensive, systematic and thorough resource of the age-dependent alterations of the mammalian immune system in lymphoid, barrier and solid tissues.
    DOI:  https://doi.org/10.1038/s43587-021-00148-x
  51. Nat Neurosci. 2023 Apr 24.
    Complex topology meets simple statistics.
    Shiyu Wang, Catie Chang.
      
    DOI:  https://doi.org/10.1038/s41593-023-01295-7
  52. J Exp Med. 2023 Aug 07. pii: e20230088. [Epub ahead of print]220(8):
    Secretory MPP3 reinforce myeloid differentiation trajectory and amplify myeloid cell production.
    Yoon-A Kang, Hyojung Paik, Si Yi Zhang, Jonathan J Chen, Oakley C Olson, Carl A Mitchell, Amelie Collins, James W Swann, Matthew R Warr, Rong Fan, Emmanuelle Passegué.
      Hematopoietic stem cells (HSC) and downstream lineage-biased multipotent progenitors (MPP) tailor blood production and control myelopoiesis on demand. Recent lineage tracing analyses revealed MPPs to be major functional contributors to steady-state hematopoiesis. However, we still lack a precise resolution of myeloid differentiation trajectories and cellular heterogeneity in the MPP compartment. Here, we found that myeloid-biased MPP3 are functionally and molecularly heterogeneous, with a distinct subset of myeloid-primed secretory cells with high endoplasmic reticulum (ER) volume and FcγR expression. We show that FcγR+/ERhigh MPP3 are a transitional population serving as a reservoir for rapid production of granulocyte/macrophage progenitors (GMP), which directly amplify myelopoiesis through inflammation-triggered secretion of cytokines in the local bone marrow (BM) microenvironment. Our results identify a novel regulatory function for a secretory MPP3 subset that controls myeloid differentiation through lineage-priming and cytokine production and acts as a self-reinforcing amplification compartment in inflammatory stress and disease conditions.
    DOI:  https://doi.org/10.1084/jem.20230088
  53. Nat Aging. 2022 Aug;2(8): 742-755
    Nuclear morphology is a deep learning biomarker of cellular senescence.
    Indra Heckenbach, Garik V Mkrtchyan, Michael Ben Ezra, Daniela Bakula, Jakob Sture Madsen, Malte Hasle Nielsen, Denise Oró, Brenna Osborne, Anthony J Covarrubias, M Laura Idda, Myriam Gorospe, Laust Mortensen, Eric Verdin, Rudi Westendorp, Morten Scheibye-Knudsen.
      Cellular senescence is an important factor in aging and many age-related diseases, but understanding its role in health is challenging due to the lack of exclusive or universal markers. Using neural networks, we predict senescence from the nuclear morphology of human fibroblasts with up to 95% accuracy, and investigate murine astrocytes, murine neurons, and fibroblasts with premature aging in culture. After generalizing our approach, the predictor recognizes higher rates of senescence in p21-positive and ethynyl-2'-deoxyuridine (EdU)-negative nuclei in tissues and shows an increasing rate of senescent cells with age in H&E-stained murine liver tissue and human dermal biopsies. Evaluating medical records reveals that higher rates of senescent cells correspond to decreased rates of malignant neoplasms and increased rates of osteoporosis, osteoarthritis, hypertension and cerebral infarction. In sum, we show that morphological alterations of the nucleus can serve as a deep learning predictor of senescence that is applicable across tissues and species and is associated with health outcomes in humans.
    DOI:  https://doi.org/10.1038/s43587-022-00263-3
  54. Nat Commun. 2023 Apr 24. 14(1): 2344
    Associations between in vitro, in vivo and in silico cell classes in mouse primary visual cortex.
    Yina Wei, Anirban Nandi, Xiaoxuan Jia, Joshua H Siegle, Daniel Denman, Soo Yeun Lee, Anatoly Buchin, Werner Van Geit, Clayton P Mosher, Shawn Olsen, Costas A Anastassiou.
      The brain consists of many cell classes yet in vivo electrophysiology recordings are typically unable to identify and monitor their activity in the behaving animal. Here, we employed a systematic approach to link cellular, multi-modal in vitro properties from experiments with in vivo recorded units via computational modeling and optotagging experiments. We found two one-channel and six multi-channel clusters in mouse visual cortex with distinct in vivo properties in terms of activity, cortical depth, and behavior. We used biophysical models to map the two one- and the six multi-channel clusters to specific in vitro classes with unique morphology, excitability and conductance properties that explain their distinct extracellular signatures and functional characteristics. These concepts were tested in ground-truth optotagging experiments with two inhibitory classes unveiling distinct in vivo properties. This multi-modal approach presents a powerful way to separate in vivo clusters and infer their cellular properties from first principles.
    DOI:  https://doi.org/10.1038/s41467-023-37844-8
  55. Nat Aging. 2022 Jun;2(6): 548-561
    Inference of age-associated transcription factor regulatory activity changes in single cells.
    Alok K Maity, Xue Hu, Tianyu Zhu, Andrew E Teschendorff.
      Transcription factors (TFs) control cell identity and function. How their activity is altered during healthy aging is critical for an improved understanding of aging and disease risk, yet relatively little is known about such changes at cell-type resolution. Here we present and validate a TF activity estimation method for single cells from the hematopoietic system that is based on TF regulons, and apply it to a mouse single-cell RNA-sequencing atlas, to infer age-associated differentiation activity changes in the immune cells of different organs. This revealed an age-associated signature of macrophage dedifferentiation, which is shared across tissue types, and aggravated in tumor-associated macrophages. By extending the analysis to all major cell types, we reveal cell-type and tissue-type-independent age-associated alterations to regulatory factors controlling antigen processing, inflammation, collagen processing and circadian rhythm, that are implicated in age-related diseases. Finally, our study highlights the limitations of using TF expression to infer age-associated changes, underscoring the need to use regulatory activity inference methods.
    DOI:  https://doi.org/10.1038/s43587-022-00233-9
  56. Nat Aging. 2021 May;1(5): 438-453
    Aging-associated lncRNAs are evolutionarily conserved and participate in NFκB signaling.
    Donghong Cai, Jing-Dong J Han.
      The transcriptome undergoes global changes during aging, including both protein-coding and noncoding RNAs. Using comparative genomics, we identify aging-associated long noncoding RNAs (lncRNAs) that are under evolutionary constraint and are more conserved than lncRNAs that do not change with age. Aging-associated lncRNAs are enriched for functional elements, including binding sites for RNA-binding proteins and transcription factors, in particular nuclear factor kappa B (NFκB). Using CRISPR screening, we discovered that 13 of the aging-associated lncRNAs were regulators of the NFκB pathway, and we named this family 'NFκB modulating aging-related lncRNAs (NFKBMARLs)'. Further characterization of NFκBMARL-1 reveals it can be traced to 29 Ma before humans and is induced by NFκB during aging, inflammation and senescence. Reciprocally, NFκBMARL-1 directly regulates transcription of the NFκB inhibitor NFKBIZ in cis within the same topologically associated domain by binding to the NFKBIZ enhancer and recruiting RELA to the NFKBIZ promoter. These findings reveal many aging-associated lncRNAs are evolutionarily conserved components of the NFκB pathway.
    DOI:  https://doi.org/10.1038/s43587-021-00056-0
  57. Nat Commun. 2023 Apr 26. 14(1): 2407
    Overcoming adaptive resistance to anti-VEGF therapy by targeting CD5L.
    Christopher J LaFargue, Paola Amero, Kyunghee Noh, Lingegowda S Mangala, Yunfei Wen, Emine Bayraktar, Sujanitha Umamaheswaran, Elaine Stur, Santosh K Dasari, Cristina Ivan, Sunila Pradeep, Wonbeak Yoo, Chunhua Lu, Nicholas B Jennings, Vinod Vathipadiekal, Wei Hu, Anca Chelariu-Raicu, Zhiqiang Ku, Hui Deng, Wei Xiong, Hyun-Jin Choi, Min Hu, Takae Kiyama, Chai-An Mao, Rouba Ali-Fehmi, Michael J Birrer, Jinsong Liu, Ningyan Zhang, Gabriel Lopez-Berestein, Vittorio de Franciscis, Zhiqiang An, Anil K Sood.
      Antiangiogenic treatment targeting the vascular endothelial growth factor (VEGF) pathway is a powerful tool to combat tumor growth and progression; however, drug resistance frequently emerges. We identify CD5L (CD5 antigen-like precursor) as an important gene upregulated in response to antiangiogenic therapy leading to the emergence of adaptive resistance. By using both an RNA-aptamer and a monoclonal antibody targeting CD5L, we are able to abate the pro-angiogenic effects of CD5L overexpression in both in vitro and in vivo settings. In addition, we find that increased expression of vascular CD5L in cancer patients is associated with bevacizumab resistance and worse overall survival. These findings implicate CD5L as an important factor in adaptive resistance to antiangiogenic therapy and suggest that modalities to target CD5L have potentially important clinical utility.
    DOI:  https://doi.org/10.1038/s41467-023-36910-5
  58. Nat Aging. 2023 Apr;3(4): 402-417
    Spurious intragenic transcription is a feature of mammalian cellular senescence and tissue aging.
    Payel Sen, Greg Donahue, Catherine Li, Gabor Egervari, Na Yang, Yemin Lan, Neil Robertson, Parisha P Shah, Erik Kerkhoven, David C Schultz, Peter D Adams, Shelley L Berger.
      Mammalian aging is characterized by the progressive loss of tissue function and increased risk for disease. Accumulation of senescent cells in aging tissues partly contributes to this decline, and targeted depletion of senescent cells in vivo ameliorates many age-related phenotypes. The fundamental molecular mechanisms responsible for the decline of cellular health and fitness during senescence and aging are largely unknown. In this study, we investigated whether chromatin-mediated loss of transcriptional fidelity, known to contribute to fitness and survival in yeast and worms, also occurs during human cellular senescence and mouse aging. Our findings reveal aberrant transcription initiation inside genes during senescence and aging that co-occurs with changes in the chromatin landscape. Interventions that alter these spurious transcripts have profound consequences on cellular health, primarily affecting intracellular signal transduction pathways. We propose that age-related spurious transcription promotes a noisy transcriptome and degradation of coherent transcriptional networks.
    DOI:  https://doi.org/10.1038/s43587-023-00384-3
  59. Mol Cell. 2023 Apr 26. pii: S1097-2765(23)00249-6. [Epub ahead of print]
    A hyper-quiescent chromatin state formed during aging is reversed by regeneration.
    Na Yang, James R Occean, Daniël P Melters, Changyou Shi, Lin Wang, Stephanie Stransky, Maire E Doyle, Chang-Yi Cui, Michael Delannoy, Jinshui Fan, Eliza Slama, Josephine M Egan, Supriyo De, Steven C Cunningham, Rafael de Cabo, Simone Sidoli, Yamini Dalal, Payel Sen.
      Epigenetic alterations are a key hallmark of aging but have been limitedly explored in tissues. Here, using naturally aged murine liver as a model and extending to other quiescent tissues, we find that aging is driven by temporal chromatin alterations that promote a refractory cellular state and compromise cellular identity. Using an integrated multi-omics approach and the first direct visualization of aged chromatin, we find that globally, old cells show H3K27me3-driven broad heterochromatinization and transcriptional suppression. At the local level, site-specific loss of H3K27me3 over promoters of genes encoding developmental transcription factors leads to expression of otherwise non-hepatocyte markers. Interestingly, liver regeneration reverses H3K27me3 patterns and rejuvenates multiple molecular and physiological aspects of the aged liver.
    Keywords:  aging; chromatin; epigenetics; liver; regeneration
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.005
  60. Nature. 2023 Apr 26.
    A druggable copper-signalling pathway that drives inflammation.
    Stéphanie Solier, Sebastian Müller, Tatiana Cañeque, Antoine Versini, Arnaud Mansart, Fabien Sindikubwabo, Leeroy Baron, Laila Emam, Pierre Gestraud, G Dan Pantoș, Vincent Gandon, Christine Gaillet, Ting-Di Wu, Florent Dingli, Damarys Loew, Sylvain Baulande, Sylvère Durand, Valentin Sencio, Cyril Robil, François Trottein, David Péricat, Emmanuelle Näser, Céline Cougoule, Etienne Meunier, Anne-Laure Bègue, Hélène Salmon, Nicolas Manel, Alain Puisieux, Sarah Watson, Mark A Dawson, Nicolas Servant, Guido Kroemer, Djillali Annane, Raphaël Rodriguez.
      Inflammation is a complex physiological process triggered in response to harmful stimuli1. It involves cells of the immune system capable of clearing sources of injury and damaged tissues. Excessive inflammation can occur as a result of infection and is a hallmark of several diseases2-4. The molecular bases underlying inflammatory responses are not fully understood. Here we show that the cell surface glycoprotein CD44, which marks the acquisition of distinct cell phenotypes in the context of development, immunity and cancer progression, mediates the uptake of metals including copper. We identify a pool of chemically reactive copper(II) in mitochondria of inflammatory macrophages that catalyses NAD(H) redox cycling by activating hydrogen peroxide. Maintenance of NAD+ enables metabolic and epigenetic programming towards the inflammatory state. Targeting mitochondrial copper(II) with supformin (LCC-12), a rationally designed dimer of metformin, induces a reduction of the NAD(H) pool, leading to metabolic and epigenetic states that oppose macrophage activation. LCC-12 interferes with cell plasticity in other settings and reduces inflammation in mouse models of bacterial and viral infections. Our work highlights the central role of copper as a regulator of cell plasticity and unveils a therapeutic strategy based on metabolic reprogramming and the control of epigenetic cell states.
    DOI:  https://doi.org/10.1038/s41586-023-06017-4
  61. Nat Methods. 2023 Apr 27.
    Photoselective sequencing: microscopically guided genomic measurements with subcellular resolution.
    Sarah M Mangiameli, Haiqi Chen, Andrew S Earl, Julie A Dobkin, Daniel Lesman, Jason D Buenrostro, Fei Chen.
      In biological systems, spatial organization and function are interconnected. Here we present photoselective sequencing, a new method for genomic and epigenomic profiling within morphologically distinct regions. Starting with an intact biological specimen, photoselective sequencing uses targeted illumination to selectively unblock a photocaged fragment library, restricting the sequencing-based readout to microscopically identified spatial regions. We validate photoselective sequencing by measuring the chromatin accessibility profiles of fluorescently labeled cell types within the mouse brain and comparing with published data. Furthermore, by combining photoselective sequencing with a computational strategy for decomposing bulk accessibility profiles, we find that the oligodendrocyte-lineage-cell population is relatively enriched for oligodendrocyte-progenitor cells in the cortex versus the corpus callosum. Finally, we leverage photoselective sequencing at the subcellular scale to identify features of chromatin that are correlated with positioning at the nuclear periphery. These results collectively demonstrate that photoselective sequencing is a flexible and generalizable platform for exploring the interplay of spatial structures with genomic and epigenomic properties.
    DOI:  https://doi.org/10.1038/s41592-023-01845-8
  62. Nat Commun. 2023 Apr 27. 14(1): 2430
    HMGN1 enhances CRISPR-directed dual-function A-to-G and C-to-G base editing.
    Chao Yang, Zhenzhen Ma, Keshan Wang, Xingxiao Dong, Meiyu Huang, Yaqiu Li, Xiagu Zhu, Ju Li, Zhihui Cheng, Changhao Bi, Xueli Zhang.
      C-to-G base editors have been successfully constructed recently, but limited work has been done on concurrent C-to-G and A-to-G base editing. In addition, there is also limited data on how chromatin-associated factors affect the base editing. Here, we test a series of chromatin-associated factors, and chromosomal protein HMGN1 was found to enhance the efficiency of both C-to-G and A-to-G base editing. By fusing HMGN1, GBE and ABE to Cas9, we develop a CRISPR-based dual-function A-to-G and C-to-G base editor (GGBE) which is capable of converting simultaneous A and C to G conversion with substantial editing efficiency. Accordingly, the HMGN1 role shown in this work and the resulting GGBE tool further broaden the genome manipulation capacity of CRISPR-directed base editors.
    DOI:  https://doi.org/10.1038/s41467-023-38193-2
  63. Nat Neurosci. 2023 Apr 24.
    Tau activation of microglial cGAS-IFN reduces MEF2C-mediated cognitive resilience.
    Joe C Udeochu, Sadaf Amin, Yige Huang, Li Fan, Eileen Ruth S Torres, Gillian K Carling, Bangyan Liu, Hugo McGurran, Guillermo Coronas-Samano, Grant Kauwe, Gergey Alzaem Mousa, Man Ying Wong, Pearly Ye, Ravi Kumar Nagiri, Iris Lo, Julia Holtzman, Carlo Corona, Allan Yarahmady, Michael T Gill, Ravikiran M Raju, Sue-Ann Mok, Shiaoching Gong, Wenjie Luo, Mingrui Zhao, Tara E Tracy, Rajiv R Ratan, Li-Huei Tsai, Subhash C Sinha, Li Gan.
      Pathological hallmarks of Alzheimer's disease (AD) precede clinical symptoms by years, indicating a period of cognitive resilience before the onset of dementia. Here, we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of Cgas in mice with tauopathy diminished the microglial IFN-I response, preserved synapse integrity and plasticity and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation increased, while activation of IFN-I decreased, the neuronal MEF2C expression network linked to cognitive resilience in AD. Pharmacological inhibition of cGAS in mice with tauopathy enhanced the neuronal MEF2C transcriptional network and restored synaptic integrity, plasticity and memory, supporting the therapeutic potential of targeting the cGAS-IFN-MEF2C axis to improve resilience against AD-related pathological insults.
    DOI:  https://doi.org/10.1038/s41593-023-01315-6
  64. J Clin Invest. 2023 Apr 25. pii: e165933. [Epub ahead of print]
    DPP4 inhibition impairs senohemostasis to improve plaque stability in atherosclerotic mice.
    Allison B Herman, Dimitrios Tsitsipatis, Carlos Anerillas, Krystyna Mazan-Mamczarz, Angelica E Carr, Jordan M Gregg, Mingyi Wang, Jing Zhang, Marc Michel, Charnae' Henry-Smith, Sophia C Harris, Rachel Munk, Jennifer L Martindale, Yulan Piao, Jinshui Fan, Julie A Mattison, Supriyo De, Kotb Abdelmohsen, Robert W Maul, Toshiko Tanaka, Ann Z Moore, Megan E DeMouth, Simone Sidoli, Luigi Ferrucci, Yie Liu, Rafael de Cabo, Edward G Lakatta, Myriam Gorospe.
      Senescent vascular smooth muscle cells (VSMCs) accumulate in the vasculature with age and tissue damage, and secrete factors that promote atherosclerotic plaque vulnerability and disease. Here, we report increased levels and activity of dipeptidyl peptidase 4 (DPP4), a serine protease, in senescent VSMCs. Analysis of the conditioned media from senescent VSMCs revealed a unique senescence-associated secretory phenotype (SASP) signature comprising many complement and coagulation factors; silencing or inhibiting DPP4 reduced these factors and increased cell death. Serum samples from persons with high risk for cardiovascular disease contained high levels of DPP4-regulated complement and coagulation factors. Importantly, DPP4 inhibition reduced senescent cell burden and coagulation and improved plaque stability, while single-cell resolution of senescent VSMCs reflected the senomorphic and senolytic effects of DPP4 inhibition in murine atherosclerosis. We propose that DPP4-regulated factors could be exploited therapeutically to reduce senescent cell function, reverse senohemostasis, and improve vascular disease.
    Keywords:  Aging; Atherosclerosis; Cellular senescence; Vascular Biology
    DOI:  https://doi.org/10.1172/JCI165933
  65. Nat Commun. 2023 Apr 22. 14(1): 2331
    In vivo bioluminescence imaging of natural bacteria within deep tissues via ATP-binding cassette sugar transporter.
    Qian Zhang, Bin Song, Yanan Xu, Yunmin Yang, Jian Ji, Wenjun Cao, Jianping Lu, Jiali Ding, Haiting Cao, Binbin Chu, Jiaxu Hong, Houyu Wang, Yao He.
      Most existing bioluminescence imaging methods can only visualize the location of engineered bacteria in vivo, generally precluding the imaging of natural bacteria. Herein, we leverage bacteria-specific ATP-binding cassette sugar transporters to internalize luciferase and luciferin by hitchhiking them on the unique carbon source of bacteria. Typically, the synthesized bioluminescent probes are made of glucose polymer (GP), luciferase, Cy5 and ICG-modified silicon nanoparticles and their substrates are made of GP and D-luciferin-modified silicon nanoparticles. Compared with bacteria with mutations in transporters, which hardly internalize the probes in vitro (i.e., ~2% of uptake rate), various bacteria could robustly engulf the probes with a high uptake rate of around 50%. Notably, the developed strategy enables ex vivo bioluminescence imaging of human vitreous containing ten species of pathogens collected from patients with bacterial endophthalmitis. By using this platform, we further differentiate bacterial and non-bacterial nephritis and colitis in mice, while their chemiluminescent counterparts are unable to distinguish them.
    DOI:  https://doi.org/10.1038/s41467-023-37827-9
  66. Nat Aging. 2022 Mar;2(3): 199-213
    Pleiotropic effects of mitochondria in aging.
    Tanes Lima, Terytty Yang Li, Adrienne Mottis, Johan Auwerx.
      Aging is typified by a progressive decline in mitochondrial activity and stress resilience. Here, we review how mitochondrial stress pathways have pleiotropic effects on cellular and systemic homeostasis, which can comprise protective or detrimental responses during aging. We describe recent evidence arguing that defects in these conserved adaptive pathways contribute to aging and age-related diseases. Signaling pathways regulating the mitochondrial unfolded protein response, mitochondrial membrane dynamics, and mitophagy are discussed, emphasizing how their failure contributes to heteroplasmy and de-regulation of key metabolites. Our current understanding of how these processes are controlled and interconnected explains how mitochondria can widely impact fundamental aspects of aging.
    DOI:  https://doi.org/10.1038/s43587-022-00191-2
  67. Nat Aging. 2022 May;2(5): 397-411
    In vivo cyclic induction of the FOXM1 transcription factor delays natural and progeroid aging phenotypes and extends healthspan.
    Rui Ribeiro, Joana C Macedo, Madalena Costa, Vladimir Ustiyan, Anastasia V Shindyapina, Alexander Tyshkovskiy, Rita N Gomes, José Pedro Castro, Tanya V Kalin, Francisco Vasques-Nóvoa, Diana S Nascimento, Sergey E Dmitriev, Vadim N Gladyshev, Vladimir V Kalinichenko, Elsa Logarinho.
      The FOXM1 transcription factor exhibits pleiotropic C-terminal transcriptional and N-terminal non-transcriptional functions in various biological processes critical for cellular homeostasis. We previously found that FOXM1 repression during cellular aging underlies the senescence phenotypes, which were vastly restored by overexpressing transcriptionally active FOXM1. Yet, it remains unknown whether increased expression of FOXM1 can delay organismal aging. Here, we show that in vivo cyclic induction of an N-terminal truncated FOXM1 transgene on progeroid and naturally aged mice offsets aging-associated repression of full-length endogenous Foxm1, reinstating both transcriptional and non-transcriptional functions. This translated into mitigation of several cellular aging hallmarks, as well as molecular and histopathological progeroid features of the short-lived Hutchison-Gilford progeria mouse model, significantly extending its lifespan. FOXM1 transgene induction also reinstated endogenous Foxm1 levels in naturally aged mice, delaying aging phenotypes while extending their lifespan. Thus, we disclose that FOXM1 genetic rewiring can delay senescence-associated progeroid and natural aging pathologies.
    DOI:  https://doi.org/10.1038/s43587-022-00209-9
  68. Nat Commun. 2023 Apr 27. 14(1): 2425
    RNA-mediated demixing transition of low-density condensates.
    Taehyun Kim, Jaeyoon Yoo, Sungho Do, Dong Soo Hwang, YongKeun Park, Yongdae Shin.
      Biomolecular condensates play a key role in organizing cellular reactions by concentrating a specific set of biomolecules. However, whether condensate formation is accompanied by an increase in the total mass concentration within condensates or by the demixing of already highly crowded intracellular components remains elusive. Here, using refractive index imaging, we quantify the mass density of several condensates, including nucleoli, heterochromatin, nuclear speckles, and stress granules. Surprisingly, the latter two condensates exhibit low densities with a total mass concentration similar to the surrounding cyto- or nucleoplasm. Low-density condensates display higher permeability to cellular protein probes. We find that RNA tunes the biomolecular density of condensates. Moreover, intracellular structures such as mitochondria heavily influence the way phase separation proceeds, impacting the localization, morphology, and growth of condensates. These findings favor a model where segregative phase separation driven by non-associative or repulsive molecular interactions together with RNA-mediated selective association of specific components can give rise to low-density condensates in the crowded cellular environment.
    DOI:  https://doi.org/10.1038/s41467-023-38118-z
  69. Nat Aging. 2022 Dec;2(12): 1159-1175
    Sphingolipids accumulate in aged muscle, and their reduction counteracts sarcopenia.
    Pirkka-Pekka Laurila, Martin Wohlwend, Tanes Imamura de Lima, Peiling Luan, Sébastien Herzig, Nadège Zanou, Barbara Crisol, Maroun Bou-Sleiman, Eleonora Porcu, Hector Gallart-Ayala, Michal K Handzlik, Qi Wang, Suresh Jain, Davide D'Amico, Minna Salonen, Christian M Metallo, Zoltan Kutalik, Thomas O Eichmann, Nicolas Place, Julijana Ivanisevic, Jari Lahti, Johan G Eriksson, Johan Auwerx.
      Age-related muscle dysfunction and sarcopenia are major causes of physical incapacitation in older adults and currently lack viable treatment strategies. Here we find that sphingolipids accumulate in mouse skeletal muscle upon aging and that both genetic and pharmacological inhibition of sphingolipid synthesis prevent age-related decline in muscle mass while enhancing strength and exercise capacity. Inhibition of sphingolipid synthesis confers increased myogenic potential and promotes protein synthesis. Within the sphingolipid pathway, we show that accumulation of dihydroceramides is the culprit disturbing myofibrillar homeostasis. The relevance of sphingolipid pathways in human aging is demonstrated in two cohorts, the UK Biobank and Helsinki Birth Cohort Study in which gene expression-reducing variants of SPTLC1 and DEGS1 are associated with improved and reduced fitness of older individuals, respectively. These findings identify sphingolipid synthesis inhibition as an attractive therapeutic strategy for age-related sarcopenia and co-occurring pathologies.
    DOI:  https://doi.org/10.1038/s43587-022-00309-6
  70. Nat Aging. 2023 Feb;3(2): 202-212
    Activation of innate immune cGAS-STING pathway contributes to Alzheimer's pathogenesis in 5×FAD mice.
    Xiaochun Xie, Guanqin Ma, Xiaohong Li, Jiebin Zhao, Zhen Zhao, Jianxiong Zeng.
      cGAS senses microbial and host-derived double-stranded DNA in cytoplasm to trigger cellular innate immune response in a STING-dependent manner; however, it remains unknown whether the cGAS-STING pathway in innate immunity contributes to Alzheimer's disease (AD). Here we demonstrated the detectable binding of the cGAS double-stranded DNA in cytoplasm and the activation of the microglial cGAS-STING pathway in brains of human AD and aged mice. Cgas-/-;5×FAD mice were largely protected from cognitive impairment, amyloid-β pathology, neuroinflammation and other sequelae associated with AD. Furthermore, Cgas deficiency in microglia inhibited a neurotoxic A1 astrocytic phenotype and thus alleviated oligomeric amyloid-β peptide-induced neurotoxicity. Finally, administration of STING inhibitor H-151 potently suppressed the activation of the cGAS-STING pathway and ameliorated AD pathogenesis in 5×FAD mice. In conclusion, our present study has identified a critical molecular link between innate immunity and AD and suggests that therapeutic targeting of the cGAS-STING pathway activity might effectively interfere with the progression of AD.
    DOI:  https://doi.org/10.1038/s43587-022-00337-2
  71. Nat Aging. 2023 Mar;3(3): 258-274
    Age-related liver endothelial zonation triggers steatohepatitis by inactivating pericentral endothelium-derived C-kit.
    Juan-Li Duan, Jing-Jing Liu, Bai Ruan, Jian Ding, Zhi-Qiang Fang, Hao Xu, Ping Song, Chen Xu, Zhi-Wen Li, Wei Du, Ming Xu, Yu-Wei Ling, Fei He, Lin Wang.
      Aging leads to systemic metabolic disorders, including steatosis. Here we show that liver sinusoidal endothelial cell (LSEC) senescence accelerates liver sinusoid capillarization and promotes steatosis by reprogramming liver endothelial zonation and inactivating pericentral endothelium-derived C-kit, which is a type III receptor tyrosine kinase. Specifically, inhibition of endothelial C-kit triggers cellular senescence, perturbing LSEC homeostasis in male mice. During diet-induced nonalcoholic steatohepatitis (NASH) development, Kit deletion worsens hepatic steatosis and exacerbates NASH-associated fibrosis and inflammation. Mechanistically, C-kit transcriptionally inhibits chemokine (C-X-C motif) receptor (CXCR)4 via CCAAT enhancer-binding protein α (CEBPA). Blocking CXCR4 signaling abolishes LSEC-macrophage-neutrophil cross-talk and leads to the recovery of C-kit-deficient mice with NASH. Of therapeutic relevance, infusing C-kit-expressing LSECs into aged mice or mice with diet-induced NASH counteracts age-associated senescence and steatosis and improves the symptoms of diet-induced NASH by restoring metabolic homeostasis of the pericentral liver endothelium. Our work provides an alternative approach that could be useful for treating aging- and diet-induced NASH.
    DOI:  https://doi.org/10.1038/s43587-022-00348-z
  72. Nat Med. 2023 Apr 27.
    The transcriptional and regulatory identity of erythropoietin producing cells.
    Bjørt K Kragesteen, Amir Giladi, Eyal David, Shahar Halevi, Laufey Geirsdóttir, Olga M Lempke, Baoguo Li, Andreas M Bapst, Ken Xie, Yonatan Katzenelenbogen, Sophie L Dahl, Fadi Sheban, Anna Gurevich-Shapiro, Mor Zada, Truong San Phan, Roberto Avellino, Shuang-Yin Wang, Oren Barboy, Shir Shlomi-Loubaton, Sandra Winning, Philipp P Markwerth, Snir Dekalo, Hadas Keren-Shaul, Merav Kedmi, Martin Sikora, Joachim Fandrey, Thorfinn S Korneliussen, Josef T Prchal, Barak Rosenzweig, Vladimir Yutkin, Fernando Racimo, Eske Willerslev, Chamutal Gur, Roland H Wenger, Ido Amit.
      Erythropoietin (Epo) is the master regulator of erythropoiesis and oxygen homeostasis. Despite its physiological importance, the molecular and genomic contexts of the cells responsible for renal Epo production remain unclear, limiting more-effective therapies for anemia. Here, we performed single-cell RNA and transposase-accessible chromatin (ATAC) sequencing of an Epo reporter mouse to molecularly identify Epo-producing cells under hypoxic conditions. Our data indicate that a distinct population of kidney stroma, which we term Norn cells, is the major source of endocrine Epo production in mice. We use these datasets to identify the markers, signaling pathways and transcriptional circuits characteristic of Norn cells. Using single-cell RNA sequencing and RNA in situ hybridization in human kidney tissues, we further provide evidence that this cell population is conserved in humans. These preliminary findings open new avenues to functionally dissect EPO gene regulation in health and disease and may serve as groundwork to improve erythropoiesis-stimulating therapies.
    DOI:  https://doi.org/10.1038/s41591-023-02314-7
  73. Nat Aging. 2023 Apr 17.
    CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.
    Jun Jin, Yunmei Mu, Huimin Zhang, Ines Sturmlechner, Chenyao Wang, Rohit R Jadhav, Qiong Xia, Cornelia M Weyand, Jorg J Goronzy.
      Chronic systemic inflammation is one of the hallmarks of the aging immune system. Here we show that activated T cells from older adults contribute to inflammaging by releasing mitochondrial DNA (mtDNA) into their environment due to an increased expression of the cytokine-inducible SH2-containing protein (CISH). CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation, thereby impairing lysosomal function. Impaired lysosomal activity caused intracellular accumulation of multivesicular bodies and amphisomes and the export of their cargos, including mtDNA. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal release. In antigen-specific responses in vivo, CISH-deficient CD4+ T cells released less mtDNA and induced fewer inflammatory cytokines. Attenuating CISH expression may present a promising strategy to reduce inflammation in an immune response of older individuals.
    DOI:  https://doi.org/10.1038/s43587-023-00399-w
  74. Nat Aging. 2021 Sep;1(9): 783-794
    Rare genetic coding variants associated with human longevity and protection against age-related diseases.
    Regeneron Genetics Center
      Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on individuals harboring the known common risk allele APOE4. The genetic component of extreme human longevity constitutes, at least in part, rare coding variants in pathways that protect against aging, including those that control longevity in model organisms.
    DOI:  https://doi.org/10.1038/s43587-021-00108-5
  75. Nat Aging. 2023 Mar;3(3): 313-326
    Skeletal muscle mitochondrial interactome remodeling is linked to functional decline in aged female mice.
    Anna A Bakhtina, Gavin A Pharaoh, Matthew D Campbell, Andrew Keller, Rudolph S Stuppard, David J Marcinek, James E Bruce.
      Genomic, transcriptomic and proteomic approaches have been used to gain insight into molecular underpinnings of aging in laboratory animals and in humans. However, protein function in biological systems is under complex regulation and includes factors besides abundance levels, such as modifications, localization, conformation and protein-protein interactions. By making use of quantitative chemical cross-linking technologies, we show that changes in the muscle mitochondrial interactome contribute to mitochondrial functional decline in aging in female mice. Specifically, we identify age-related changes in protein cross-links relating to assembly of electron transport system complexes I and IV, activity of glutamate dehydrogenase, and coenzyme-A binding in fatty acid β-oxidation and tricarboxylic acid cycle enzymes. These changes show a remarkable correlation with complex I respiration differences within the same young-old animal pairs. Each observed cross-link can serve as a protein conformational or protein-protein interaction probe in future studies, which will provide further molecular insights into commonly observed age-related phenotypic differences. Therefore, this data set could become a valuable resource for additional in-depth molecular studies that are needed to better understand complex age-related molecular changes.
    DOI:  https://doi.org/10.1038/s43587-023-00366-5
  76. Cell. 2023 Apr 14. pii: S0092-8674(23)00327-6. [Epub ahead of print]
    Mesoscale DNA feature in antibody-coding sequence facilitates somatic hypermutation.
    Yanyan Wang, Senxin Zhang, Xinrui Yang, Joyce K Hwang, Chuanzong Zhan, Chaoyang Lian, Chong Wang, Tuantuan Gui, Binbin Wang, Xia Xie, Pengfei Dai, Lu Zhang, Ying Tian, Huizhi Zhang, Chong Han, Yanni Cai, Qian Hao, Xiaofei Ye, Xiaojing Liu, Jiaquan Liu, Zhiwei Cao, Shaohui Huang, Jie Song, Qiang Pan-Hammarström, Yaofeng Zhao, Frederick W Alt, Xiaoqi Zheng, Lin-Tai Da, Leng-Siew Yeap, Fei-Long Meng.
      Somatic hypermutation (SHM), initiated by activation-induced cytidine deaminase (AID), generates mutations in the antibody-coding sequence to allow affinity maturation. Why these mutations intrinsically focus on the three nonconsecutive complementarity-determining regions (CDRs) remains enigmatic. Here, we found that predisposition mutagenesis depends on the single-strand (ss) DNA substrate flexibility determined by the mesoscale sequence surrounding AID deaminase motifs. Mesoscale DNA sequences containing flexible pyrimidine-pyrimidine bases bind effectively to the positively charged surface patches of AID, resulting in preferential deamination activities. The CDR hypermutability is mimicable in in vitro deaminase assays and is evolutionarily conserved among species using SHM as a major diversification strategy. We demonstrated that mesoscale sequence alterations tune the in vivo mutability and promote mutations in an otherwise cold region in mice. Our results show a non-coding role of antibody-coding sequence in directing hypermutation, paving the way for the synthetic design of humanized animal models for optimal antibody discovery and explaining the AID mutagenesis pattern in lymphoma.
    Keywords:  AID; affinity maturation; complementarity-determining region; deaminase; somatic hypermutation
    DOI:  https://doi.org/10.1016/j.cell.2023.03.030
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