bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023‒08‒20
fifty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Genomic map of inflammatory blood proteins.
  2. Teaching workplace skills.
  3. The brain's unique take on algorithms.
  4. Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice.
  5. p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1.
  6. Endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle.
  7. REPTOR and CREBRF encode key regulators of muscle energy metabolism.
  8. RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation.
  9. Mitochondrial DNA comes with nuclear strings attached.
  10. High-sensitive nascent transcript sequencing reveals BRD4-specific control of widespread enhancer and target gene transcription.
  11. Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo.
  12. Intrinsically disordered domain of transcription factor TCF-1 is required for T cell developmental fidelity.
  13. Atlas of the aging mouse brain reveals white matter as vulnerable foci.
  14. Nuclear genetic control of mtDNA copy number and heteroplasmy in humans.
  15. FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1.
  16. Multicolor lifetime imaging and its application to HIV-1 uptake.
  17. Platelet factors attenuate inflammation and rescue cognition in ageing.
  18. Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models.
  19. Integrin β3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis.
  20. Mapping the T cell repertoire to a complex gut bacterial community.
  21. The pitfalls of interpreting hyperintense FLAIR signal as lymph outside the human brain.
  22. A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology.
  23. Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired.
  24. Spatial organization of the mouse retina at single cell resolution by MERFISH.
  25. Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion.
  26. Early-adulthood spike in protein translation drives aging via juvenile hormone/germline signaling.
  27. TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation.
  28. Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice.
  29. The road not taken en route to T cell exhaustion.
  30. Yolk sac cell atlas reveals multiorgan functions during human early development.
  31. NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates.
  32. GATA2 mitotic bookmarking is required for definitive haematopoiesis.
  33. Brain mitochondria predict a mouse's stress level.
  34. Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes.
  35. Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation.
  36. A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer's disease mouse model.
  37. Lipid saturation controls nuclear envelope function.
  38. A genetic history of continuity and mobility in the Iron Age central Mediterranean.
  39. SnapFISH: a computational pipeline to identify chromatin loops from multiplexed DNA FISH data.
  40. Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen.
  41. Subtle adversarial image manipulations influence both human and machine perception.
  42. Balancing lysosome abundance in health and disease.
  43. Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths.
  44. Quantitative real-time in-cell imaging reveals heterogeneous clusters of proteins prior to condensation.
  45. Defining cardiac functional recovery in end-stage heart failure at single-cell resolution.
  46. HIF-1α inhibition in macrophages preserves acute liver failure by reducing IL-1β production.
  47. The calvaria stands alone: Unique aspects of the skull bone marrow-meninges border.
  48. Older mouse brains rejuvenated by protein found in young blood.
  49. Single-cell multiomic analysis of thymocyte development reveals drivers of CD4+ T cell and CD8+ T cell lineage commitment.
  50. An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress.
  1. Nat Immunol. 2023 Aug 17.
    Genomic map of inflammatory blood proteins.
      
    DOI:  https://doi.org/10.1038/s41590-023-01609-8
  2. Science. 2023 Aug 18. 381(6659): 806
    Teaching workplace skills.
    Tomasz Głowacki.
      
    DOI:  https://doi.org/10.1126/science.adk2755
  3. Nat Commun. 2023 Aug 16. 14(1): 4910
    The brain's unique take on algorithms.
    James B Aimone, Ojas Parekh.
      
    DOI:  https://doi.org/10.1038/s41467-023-40535-z
  4. Nat Commun. 2023 Aug 16. 14(1): 4375
    Platelet-derived exerkine CXCL4/platelet factor 4 rejuvenates hippocampal neurogenesis and restores cognitive function in aged mice.
    Odette Leiter, David Brici, Stephen J Fletcher, Xuan Ling Hilary Yong, Jocelyn Widagdo, Nicholas Matigian, Adam B Schroer, Gregor Bieri, Daniel G Blackmore, Perry F Bartlett, Victor Anggono, Saul A Villeda, Tara L Walker.
      The beneficial effects of physical activity on brain ageing are well recognised, with exerkines, factors that are secreted into the circulation in response to exercise, emerging as likely mediators of this response. However, the source and identity of these exerkines remain unclear. Here we provide evidence that an anti-geronic exerkine is secreted by platelets. We show that platelets are activated by exercise and are required for the exercise-induced increase in hippocampal precursor cell proliferation in aged mice. We also demonstrate that increasing the systemic levels of the platelet-derived exerkine CXCL4/platelet factor 4 (PF4) ameliorates age-related regenerative and cognitive impairments in a hippocampal neurogenesis-dependent manner. Together these findings highlight the role of platelets in mediating the rejuvenating effects of exercise during physiological brain ageing.
    DOI:  https://doi.org/10.1038/s41467-023-39873-9
  5. Nat Commun. 2023 Aug 17. 14(1): 4987
    p21-activated kinase 4 suppresses fatty acid β-oxidation and ketogenesis by phosphorylating NCoR1.
    Min Yan Shi, Hwang Chan Yu, Chang Yeob Han, In Hyuk Bang, Ho Sung Park, Kyu Yun Jang, Sangkyu Lee, Jeong Bum Son, Nam Doo Kim, Byung-Hyun Park, Eun Ju Bae.
      PPARα corepressor NCoR1 is a key regulator of fatty acid β-oxidation and ketogenesis. However, its regulatory mechanism is largely unknown. Here, we report that oncoprotein p21-activated kinase 4 (PAK4) is an NCoR1 kinase. Specifically, PAK4 phosphorylates NCoR1 at T1619/T2124, resulting in an increase in its nuclear localization and interaction with PPARα, thereby repressing the transcriptional activity of PPARα. We observe impaired ketogenesis and increases in PAK4 protein and NCoR1 phosphorylation levels in liver tissues of high fat diet-fed mice, NAFLD patients, and hepatocellular carcinoma patients. Forced overexpression of PAK4 in mice represses ketogenesis and thereby increases hepatic fat accumulation, whereas genetic ablation or pharmacological inhibition of PAK4 exhibites an opposite phenotype. Interestingly, PAK4 protein levels are significantly suppressed by fasting, largely through either cAMP/PKA- or Sirt1-mediated ubiquitination and proteasome degradation. In this way, our findings provide evidence for a PAK4-NCoR1/PPARα signaling pathway that regulates fatty acid β-oxidation and ketogenesis.
    DOI:  https://doi.org/10.1038/s41467-023-40597-z
  6. Nat Commun. 2023 Aug 17. 14(1): 4989
    Endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle.
    Anastasia Sacharidou, Ken Chambliss, Jun Peng, Jose Barrera, Keiji Tanigaki, Katherine Luby-Phelps, İpek Özdemir, Sohaib Khan, Shashank R Sirsi, Sung Hoon Kim, Benita S Katzenellenbogen, John A Katzenellenbogen, Mohammed Kanchwala, Adwait A Sathe, Andrew Lemoff, Chao Xing, Kenneth Hoyt, Chieko Mineo, Philip W Shaul.
      The estrogen receptor (ER) designated ERα has actions in many cell and tissue types that impact glucose homeostasis. It is unknown if these include mechanisms in endothelial cells, which have the potential to influence relative obesity, and processes in adipose tissue and skeletal muscle that impact glucose control. Here we show that independent of impact on events in adipose tissue, endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle. Endothelial ERα-deficient male mice are glucose intolerant and insulin resistant, and in females the antidiabetogenic actions of estradiol (E2) are absent. The glucose dysregulation is due to impaired skeletal muscle glucose disposal that results from attenuated muscle insulin delivery. Endothelial ERα activation stimulates insulin transcytosis by skeletal muscle microvascular endothelial cells. Mechanistically this involves nuclear ERα-dependent upregulation of vesicular trafficking regulator sorting nexin 5 (SNX5) expression, and PI3 kinase activation that drives plasma membrane recruitment of SNX5. Thus, coupled nuclear and non-nuclear actions of ERα promote endothelial insulin transport to skeletal muscle to foster normal glucose homeostasis.
    DOI:  https://doi.org/10.1038/s41467-023-40562-w
  7. Nat Commun. 2023 Aug 15. 14(1): 4943
    REPTOR and CREBRF encode key regulators of muscle energy metabolism.
    Pedro Saavedra, Phillip A Dumesic, Yanhui Hu, Elizabeth Filine, Patrick Jouandin, Richard Binari, Sarah E Wilensky, Jonathan Rodiger, Haiyun Wang, Weihang Chen, Ying Liu, Bruce M Spiegelman, Norbert Perrimon.
      Metabolic flexibility of muscle tissue describes the adaptive capacity to use different energy substrates according to their availability. The disruption of this ability associates with metabolic disease. Here, using a Drosophila model of systemic metabolic dysfunction triggered by yorkie-induced gut tumors, we show that the transcription factor REPTOR is an important regulator of energy metabolism in muscles. We present evidence that REPTOR is activated in muscles of adult flies with gut yorkie-tumors, where it modulates glucose metabolism. Further, in vivo studies indicate that sustained activity of REPTOR is sufficient in wildtype muscles to repress glycolysis and increase tricarboxylic acid (TCA) cycle metabolites. Consistent with the fly studies, higher levels of CREBRF, the mammalian ortholog of REPTOR, reduce glycolysis in mouse myotubes while promoting oxidative metabolism. Altogether, our results define a conserved function for REPTOR and CREBRF as key regulators of muscle energy metabolism.
    DOI:  https://doi.org/10.1038/s41467-023-40595-1
  8. Nat Commun. 2023 Aug 17. 14(1): 4972
    RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation.
    Amir Kumar Singh, Ritesh Kumar, Jianyi Yin, John F Brooks Ii, Mahesh Kathania, Sandip Mukherjee, Jitendra Kumar, Kevin P Conlon, Venkatesha Basrur, Zhe Chen, Xianlin Han, Lora V Hooper, Ezra Burstein, K Venuprasad.
      Th17 cells that produce Interleukin IL-17 are pathogenic in many human diseases, including inflammatory bowel disease, but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. Here we show Raftlin1, a lipid raft protein, specifically upregulates and forms a complex with RORγt in pathogenic Th17 cells. Disruption of the RORγt-Raftlin1 complex results in the reduction of pathogenic Th17 cells in response to Citrobacter rodentium; however, there is no effect on nonpathogenic Th17 cells in response to commensal segmented filamentous bacteria. Mechanistically, we show that Raftlin1 recruits distinct phospholipids to RORγt and promotes the pathogenicity of Th17 cells. Thus, we have identified a mechanism that drives the pathogenic function of Th17 cells, which could provide a platform for advanced therapeutic strategies to dampen Th17-mediated inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41467-023-40622-1
  9. Nature. 2023 Aug 16.
    Mitochondrial DNA comes with nuclear strings attached.
    Sonia Boscenco, Ed Reznik.
      
    Keywords:  Genetics
    DOI:  https://doi.org/10.1038/d41586-023-01783-7
  10. Nat Commun. 2023 Aug 17. 14(1): 4971
    High-sensitive nascent transcript sequencing reveals BRD4-specific control of widespread enhancer and target gene transcription.
    Annkatrin Bressin, Olga Jasnovidova, Mirjam Arnold, Elisabeth Altendorfer, Filip Trajkovski, Thomas A Kratz, Joanna E Handzlik, Denes Hnisz, Andreas Mayer.
      Gene transcription by RNA polymerase II (Pol II) is under control of promoters and distal regulatory elements known as enhancers. Enhancers are themselves transcribed by Pol II correlating with their activity. How enhancer transcription is regulated and coordinated with transcription at target genes has remained unclear. Here, we developed a high-sensitive native elongating transcript sequencing approach, called HiS-NET-seq, to provide an extended high-resolution view on transcription, especially at lowly transcribed regions such as enhancers. HiS-NET-seq uncovers new transcribed enhancers in human cells. A multi-omics analysis shows that genome-wide enhancer transcription depends on the BET family protein BRD4. Specifically, BRD4 co-localizes to enhancer and promoter-proximal gene regions, and is required for elongation activation at enhancers and their genes. BRD4 keeps a set of enhancers and genes in proximity through long-range contacts. From these studies BRD4 emerges as a general regulator of enhancer transcription that may link transcription at enhancers and genes.
    DOI:  https://doi.org/10.1038/s41467-023-40633-y
  11. Nat Commun. 2023 Aug 15. 14(1): 4928
    Treatment of monogenic and digenic dominant genetic hearing loss by CRISPR-Cas9 ribonucleoprotein delivery in vivo.
    Yong Tao, Veronica Lamas, Wan Du, Wenliang Zhu, Yiran Li, Madelynn N Whittaker, John A Zuris, David B Thompson, Arun Prabhu Rameshbabu, Yilai Shu, Xue Gao, Johnny H Hu, Charles Pei, Wei-Jia Kong, Xuezhong Liu, Hao Wu, Benjamin P Kleinstiver, David R Liu, Zheng-Yi Chen.
      Mutations in Atp2b2, an outer hair cell gene, cause dominant hearing loss in humans. Using a mouse model Atp2b2Obl/+, with a dominant hearing loss mutation (Oblivion), we show that liposome-mediated in vivo delivery of CRISPR-Cas9 ribonucleoprotein complexes leads to specific editing of the Obl allele. Large deletions encompassing the Obl locus and indels were identified as the result of editing. In vivo genome editing promotes outer hair cell survival and restores their function, leading to hearing recovery. We further show that in a double-dominant mutant mouse model, in which the Tmc1 Beethoven mutation and the Atp2b2 Oblivion mutation cause digenic genetic hearing loss, Cas9/sgRNA delivery targeting both mutations leads to partial hearing recovery. These findings suggest that liposome-RNP delivery can be used as a strategy to recover hearing with dominant mutations in OHC genes and with digenic mutations in the auditory hair cells, potentially expanding therapeutics of gene editing to treat hearing loss.
    DOI:  https://doi.org/10.1038/s41467-023-40476-7
  12. Nat Immunol. 2023 Aug 17.
    Intrinsically disordered domain of transcription factor TCF-1 is required for T cell developmental fidelity.
    Naomi Goldman, Aditi Chandra, Isabelle Johnson, Matthew A Sullivan, Abhijeet R Patil, Ashley Vanderbeck, Atishay Jay, Yeqiao Zhou, Emily K Ferrari, Leland Mayne, Jennifer Aguilan, Hai-Hui Xue, Robert B Faryabi, E John Wherry, Simone Sidoli, Ivan Maillard, Golnaz Vahedi.
      In development, pioneer transcription factors access silent chromatin to reveal lineage-specific gene programs. The structured DNA-binding domains of pioneer factors have been well characterized, but whether and how intrinsically disordered regions affect chromatin and control cell fate is unclear. Here, we report that deletion of an intrinsically disordered region of the pioneer factor TCF-1 (termed L1) leads to an early developmental block in T cells. The few T cells that develop from progenitors expressing TCF-1 lacking L1 exhibit lineage infidelity distinct from the lineage diversion of TCF-1-deficient cells. Mechanistically, L1 is required for activation of T cell genes and repression of GATA2-driven genes, normally reserved to the mast cell and dendritic cell lineages. Underlying this lineage diversion, L1 mediates binding of TCF-1 to its earliest target genes, which are subject to repression as T cells develop. These data suggest that the intrinsically disordered N terminus of TCF-1 maintains T cell lineage fidelity.
    DOI:  https://doi.org/10.1038/s41590-023-01599-7
  13. Cell. 2023 Aug 08. pii: S0092-8674(23)00805-X. [Epub ahead of print]
    Atlas of the aging mouse brain reveals white matter as vulnerable foci.
    Oliver Hahn, Aulden G Foltz, Micaiah Atkins, Blen Kedir, Patricia Moran-Losada, Ian H Guldner, Christy Munson, Fabian Kern, Róbert Pálovics, Nannan Lu, Hui Zhang, Achint Kaur, Jacob Hull, John R Huguenard, Sebastian Grönke, Benoit Lehallier, Linda Partridge, Andreas Keller, Tony Wyss-Coray.
      Aging is the key risk factor for cognitive decline, yet the molecular changes underlying brain aging remain poorly understood. Here, we conducted spatiotemporal RNA sequencing of the mouse brain, profiling 1,076 samples from 15 regions across 7 ages and 2 rejuvenation interventions. Our analysis identified a brain-wide gene signature of aging in glial cells, which exhibited spatially defined changes in magnitude. By integrating spatial and single-nucleus transcriptomics, we found that glial aging was particularly accelerated in white matter compared with cortical regions, whereas specialized neuronal populations showed region-specific expression changes. Rejuvenation interventions, including young plasma injection and dietary restriction, exhibited distinct effects on gene expression in specific brain regions. Furthermore, we discovered differential gene expression patterns associated with three human neurodegenerative diseases, highlighting the importance of regional aging as a potential modulator of disease. Our findings identify molecular foci of brain aging, providing a foundation to target age-related cognitive decline.
    Keywords:  aging; dietary restriction; neurodegeneration; neurogenomics; neuroscience; single-cell biology
    DOI:  https://doi.org/10.1016/j.cell.2023.07.027
  14. Nature. 2023 Aug 16.
    Nuclear genetic control of mtDNA copy number and heteroplasmy in humans.
    Rahul Gupta, Masahiro Kanai, Timothy J Durham, Kristin Tsuo, Jason G McCoy, Anna V Kotrys, Wei Zhou, Patrick F Chinnery, Konrad J Karczewski, Sarah E Calvo, Benjamin M Neale, Vamsi K Mootha.
      Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation1. Heteroplasmy refers to the presence of a mixture of mtDNA alleles in an individual and has been associated with disease and ageing. Mechanisms underlying common variation in human heteroplasmy, and the influence of the nuclear genome on this variation, remain insufficiently explored. Here we quantify mtDNA copy number (mtCN) and heteroplasmy using blood-derived whole-genome sequences from 274,832 individuals and perform genome-wide association studies to identify associated nuclear loci. Following blood cell composition correction, we find that mtCN declines linearly with age and is associated with variants at 92 nuclear loci. We observe that nearly everyone harbours heteroplasmic mtDNA variants obeying two principles: (1) heteroplasmic single nucleotide variants tend to arise somatically and accumulate sharply after the age of 70 years, whereas (2) heteroplasmic indels are maternally inherited as mixtures with relative levels associated with 42 nuclear loci involved in mtDNA replication, maintenance and novel pathways. These loci may act by conferring a replicative advantage to certain mtDNA alleles. As an illustrative example, we identify a length variant carried by more than 50% of humans at position chrM:302 within a G-quadruplex previously proposed to mediate mtDNA transcription/replication switching2,3. We find that this variant exerts cis-acting genetic control over mtDNA abundance and is itself associated in-trans with nuclear loci encoding machinery for this regulatory switch. Our study suggests that common variation in the nuclear genome can shape variation in mtCN and heteroplasmy dynamics across the human population.
    DOI:  https://doi.org/10.1038/s41586-023-06426-5
  15. Mol Cell. 2023 Aug 17. pii: S1097-2765(23)00560-9. [Epub ahead of print]83(16): 3010-3026.e8
    FAM120A couples SREBP-dependent transcription and splicing of lipogenesis enzymes downstream of mTORC1.
    Sungyun Cho, Yujin Chun, Long He, Cuauhtemoc B Ramirez, Kripa S Ganesh, Kyungjo Jeong, Junho Song, Jin Gyu Cheong, Zhongchi Li, Jungmin Choi, Joohwan Kim, Nikos Koundouros, Fangyuan Ding, Noah Dephoure, Cholsoon Jang, John Blenis, Gina Lee.
      The mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that stimulates macromolecule synthesis through transcription, RNA processing, and post-translational modification of metabolic enzymes. However, the mechanisms of how mTORC1 orchestrates multiple steps of gene expression programs remain unclear. Here, we identify family with sequence similarity 120A (FAM120A) as a transcription co-activator that couples transcription and splicing of de novo lipid synthesis enzymes downstream of mTORC1-serine/arginine-rich protein kinase 2 (SRPK2) signaling. The mTORC1-activated SRPK2 phosphorylates splicing factor serine/arginine-rich splicing factor 1 (SRSF1), enhancing its binding to FAM120A. FAM120A directly interacts with a lipogenic transcription factor SREBP1 at active promoters, thereby bridging the newly transcribed lipogenic genes from RNA polymerase II to the SRSF1 and U1-70K-containing RNA-splicing machinery. This mTORC1-regulated, multi-protein complex promotes efficient splicing and stability of lipogenic transcripts, resulting in fatty acid synthesis and cancer cell proliferation. These results elucidate FAM120A as a critical transcription co-factor that connects mTORC1-dependent gene regulation programs for anabolic cell growth.
    Keywords:  FAM120A; RNA splicing; RNA stability; SREBP; SRPK2; SRSF1; lipid metabolism; mTOR signaling
    DOI:  https://doi.org/10.1016/j.molcel.2023.07.017
  16. Nat Commun. 2023 Aug 17. 14(1): 4994
    Multicolor lifetime imaging and its application to HIV-1 uptake.
    Tobias Starling, Irene Carlon-Andres, Maro Iliopoulou, Benedikt Kraemer, Maria Loidolt-Krueger, David J Williamson, Sergi Padilla-Parra.
      Simultaneous imaging of nine fluorescent proteins is demonstrated in a single acquisition using fluorescence lifetime imaging microscopy combined with pulsed interleaved excitation of three laser lines. Multicolor imaging employing genetically encodable fluorescent proteins permits spatio-temporal live cell imaging of multiple cues. Here, we show that multicolor lifetime imaging allows visualization of quadruple labelled human immunodeficiency viruses on host cells that in turn are also labelled with genetically encodable fluorescent proteins. This strategy permits to simultaneously visualize different sub-cellular organelles (mitochondria, cytoskeleton, and nucleus) during the process of virus entry with the potential of imaging up to nine different spectral channels in living cells.
    DOI:  https://doi.org/10.1038/s41467-023-40731-x
  17. Nature. 2023 Aug 16.
    Platelet factors attenuate inflammation and rescue cognition in ageing.
    Adam B Schroer, Patrick B Ventura, Juliana Sucharov, Rhea Misra, M K Kirsten Chui, Gregor Bieri, Alana M Horowitz, Lucas K Smith, Katriel Encabo, Imelda Tenggara, Julien Couthouis, Joshua D Gross, June M Chan, Anthony Luke, Saul A Villeda.
      Identifying therapeutics to delay, and potentially reverse, age-related cognitive decline is critical in light of the increased incidence of dementia-related disorders forecasted in the growing older population1. Here we show that platelet factors transfer the benefits of young blood to the ageing brain. Systemic exposure of aged male mice to a fraction of blood plasma from young mice containing platelets decreased neuroinflammation in the hippocampus at the transcriptional and cellular level and ameliorated hippocampal-dependent cognitive impairments. Circulating levels of the platelet-derived chemokine platelet factor 4 (PF4) (also known as CXCL4) were elevated in blood plasma preparations of young mice and humans relative to older individuals. Systemic administration of exogenous PF4 attenuated age-related hippocampal neuroinflammation, elicited synaptic-plasticity-related molecular changes and improved cognition in aged mice. We implicate decreased levels of circulating pro-ageing immune factors and restoration of the ageing peripheral immune system in the beneficial effects of systemic PF4 on the aged brain. Mechanistically, we identified CXCR3 as a chemokine receptor that, in part, mediates the cellular, molecular and cognitive benefits of systemic PF4 on the aged brain. Together, our data identify platelet-derived factors as potential therapeutic targets to abate inflammation and rescue cognition in old age.
    DOI:  https://doi.org/10.1038/s41586-023-06436-3
  18. Nat Commun. 2023 Aug 15. 14(1): 4909
    Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models.
    L G M Heezen, T Abdelaal, M van Putten, A Aartsma-Rus, A Mahfouz, P Spitali.
      Duchenne muscular dystrophy is caused by mutations in the DMD gene, leading to lack of dystrophin. Chronic muscle damage eventually leads to histological alterations in skeletal muscles. The identification of genes and cell types driving tissue remodeling is a key step to developing effective therapies. Here we use spatial transcriptomics in two Duchenne muscular dystrophy mouse models differing in disease severity to identify gene expression signatures underlying skeletal muscle pathology and to directly link gene expression to muscle histology. We perform deconvolution analysis to identify cell types contributing to histological alterations. We show increased expression of specific genes in areas of muscle regeneration (Myl4, Sparc, Hspg2), fibrosis (Vim, Fn1, Thbs4) and calcification (Bgn, Ctsk, Spp1). These findings are confirmed by smFISH. Finally, we use differentiation dynamic analysis in the D2-mdx muscle to identify muscle fibers in the present state that are predicted to become affected in the future state.
    DOI:  https://doi.org/10.1038/s41467-023-40555-9
  19. Nat Commun. 2023 Aug 16. 14(1): 4966
    Integrin β3 directly inhibits the Gα13-p115RhoGEF interaction to regulate G protein signaling and platelet exocytosis.
    Yaping Zhang, Xiaojuan Zhao, Bo Shen, Yanyan Bai, Claire Chang, Aleksandra Stojanovic, Can Wang, Andrew Mack, Gary Deng, Randal A Skidgel, Ni Cheng, Xiaoping Du.
      The integrins and G protein-coupled receptors are both fundamental in cell biology. The cross talk between these two, however, is unclear. Here we show that β3 integrins negatively regulate G protein-coupled signaling by directly inhibiting the Gα13-p115RhoGEF interaction. Furthermore, whereas β3 deficiency or integrin antagonists inhibit integrin-dependent platelet aggregation and exocytosis (granule secretion), they enhance G protein-coupled RhoA activation and integrin-independent secretion. In contrast, a β3-derived Gα13-binding peptide or Gα13 knockout inhibits G protein-coupled RhoA activation and both integrin-independent and dependent platelet secretion without affecting primary platelet aggregation. In a mouse model of myocardial ischemia/reperfusion injury in vivo, the β3-derived Gα13-binding peptide inhibits platelet secretion of granule constituents, which exacerbates inflammation and ischemia/reperfusion injury. These data establish crucial integrin-G protein crosstalk, providing a rationale for therapeutic approaches that inhibit exocytosis in platelets and possibly other cells without adverse effects associated with loss of cell adhesion.
    DOI:  https://doi.org/10.1038/s41467-023-40531-3
  20. Nature. 2023 Aug 16.
    Mapping the T cell repertoire to a complex gut bacterial community.
    Kazuki Nagashima, Aishan Zhao, Katayoon Atabakhsh, Minwoo Bae, Jamie E Blum, Allison Weakley, Sunit Jain, Xiandong Meng, Alice G Cheng, Min Wang, Steven Higginbottom, Alex Dimas, Pallavi Murugkar, Elizabeth S Sattely, James J Moon, Emily P Balskus, Michael A Fischbach.
      Certain bacterial strains from the microbiome induce a potent, antigen-specific T cell response1-5. However, the specificity of microbiome-induced T cells has not been explored at the strain level across the gut community. Here, we colonize germ-free mice with complex defined communities (roughly 100 bacterial strains) and profile T cell responses to each strain. The pattern of responses suggests that many T cells in the gut repertoire recognize several bacterial strains from the community. We constructed T cell hybridomas from 92 T cell receptor (TCR) clonotypes; by screening every strain in the community against each hybridoma, we find that nearly all the bacteria-specific TCRs show a one-to-many TCR-to-strain relationship, including 13 abundant TCR clonotypes that each recognize 18 Firmicutes. By screening three pooled bacterial genomic libraries, we discover that these 13 clonotypes share a single target: a conserved substrate-binding protein from an ATP-binding cassette transport system. Peripheral regulatory T cells and T helper 17 cells specific for an epitope from this protein are abundant in community-colonized and specific pathogen-free mice. Our work reveals that T cell recognition of commensals is focused on widely conserved, highly expressed cell-surface antigens, opening the door to new therapeutic strategies in which colonist-specific immune responses are rationally altered or redirected.
    DOI:  https://doi.org/10.1038/s41586-023-06431-8
  21. Nat Commun. 2023 Aug 16. 14(1): 4913
    The pitfalls of interpreting hyperintense FLAIR signal as lymph outside the human brain.
    Geir Ringstad, Per Kristian Eide.
      
    DOI:  https://doi.org/10.1038/s41467-023-40508-2
  22. Nat Commun. 2023 Aug 18. 14(1): 5023
    A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology.
    Parsa Akbari, Dragana Vuckovic, Luca Stefanucci, Tao Jiang, Kousik Kundu, Roman Kreuzhuber, Erik L Bao, Janine H Collins, Kate Downes, Luigi Grassi, Jose A Guerrero, Stephen Kaptoge, Julian C Knight, Stuart Meacham, Jennifer Sambrook, Denis Seyres, Oliver Stegle, Jeffrey M Verboon, Klaudia Walter, Nicholas A Watkins, John Danesh, David J Roberts, Emanuele Di Angelantonio, Vijay G Sankaran, Mattia Frontini, Stephen Burgess, Taco Kuijpers, James E Peters, Adam S Butterworth, Willem H Ouwehand, Nicole Soranzo, William J Astle.
      Blood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes-including cell-type specific measures of granularity, nucleic acid content and reactivity-in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types-variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease.
    DOI:  https://doi.org/10.1038/s41467-023-40679-y
  23. Nat Commun. 2023 Aug 18. 14(1): 5031
    Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired.
    Wenjing Liang, Shakti Sagar, Rishith Ravindran, Rita H Najor, Justin M Quiles, Liguo Chi, Rachel Y Diao, Benjamin P Woodall, Leonardo J Leon, Erika Zumaya, Jason Duran, David M Cauvi, Antonio De Maio, Eric D Adler, Åsa B Gustafsson.
      Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible for generating most of the energy needed to sustain contraction. Dysfunctional mitochondria are normally degraded via intracellular degradation pathways that converge on the lysosome. Here, we identified an alternative mechanism to eliminate mitochondria when lysosomal function is compromised. We show that lysosomal inhibition leads to increased secretion of mitochondria in large extracellular vesicles (EVs). The EVs are produced in multivesicular bodies, and their release is independent of autophagy. Deletion of the small GTPase Rab7 in cells or adult mouse heart leads to increased secretion of EVs containing ubiquitinated cargos, including intact mitochondria. The secreted EVs are captured by macrophages without activating inflammation. Hearts from aged mice or Danon disease patients have increased levels of secreted EVs containing mitochondria indicating activation of vesicular release during cardiac pathophysiology. Overall, these findings establish that mitochondria are eliminated in large EVs through the endosomal pathway when lysosomal degradation is inhibited.
    DOI:  https://doi.org/10.1038/s41467-023-40680-5
  24. Nat Commun. 2023 Aug 15. 14(1): 4929
    Spatial organization of the mouse retina at single cell resolution by MERFISH.
    Jongsu Choi, Jin Li, Salma Ferdous, Qingnan Liang, Jeffrey R Moffitt, Rui Chen.
      The visual signal processing in the retina requires the precise organization of diverse neuronal types working in concert. While single-cell omics studies have identified more than 120 different neuronal subtypes in the mouse retina, little is known about their spatial organization. Here, we generated the single-cell spatial atlas of the mouse retina using multiplexed error-robust fluorescence in situ hybridization (MERFISH). We profiled over 390,000 cells and identified all major cell types and nearly all subtypes through the integration with reference single-cell RNA sequencing (scRNA-seq) data. Our spatial atlas allowed simultaneous examination of nearly all cell subtypes in the retina, revealing 8 previously unknown displaced amacrine cell subtypes and establishing the connection between the molecular classification of many cell subtypes and their spatial arrangement. Furthermore, we identified spatially dependent differential gene expression between subtypes, suggesting the possibility of functional tuning of neuronal types based on location.
    DOI:  https://doi.org/10.1038/s41467-023-40674-3
  25. Sci Adv. 2023 Aug 18. 9(33): eadh0558
    Cross-species analysis identifies mitochondrial dysregulation as a functional consequence of the schizophrenia-associated 3q29 deletion.
    Ryan H Purcell, Esra Sefik, Erica Werner, Alexia T King, Trenell J Mosley, Megan E Merritt-Garza, Pankaj Chopra, Zachary T McEachin, Sridhar Karne, Nisha Raj, Brandon J Vaglio, Dylan Sullivan, Bonnie L Firestein, Kedamawit Tilahun, Maxine I Robinette, Stephen T Warren, Zhexing Wen, Victor Faundez, Steven A Sloan, Gary J Bassell, Jennifer G Mulle.
      The 1.6-megabase deletion at chromosome 3q29 (3q29Del) is the strongest identified genetic risk factor for schizophrenia, but the effects of this variant on neurodevelopment are not well understood. We interrogated the developing neural transcriptome in two experimental model systems with complementary advantages: isogenic human cortical organoids and isocortex from the 3q29Del mouse model. We profiled transcriptomes from isogenic cortical organoids that were aged for 2 and 12 months, as well as perinatal mouse isocortex, all at single-cell resolution. Systematic pathway analysis implicated dysregulation of mitochondrial function and energy metabolism. These molecular signatures were supported by analysis of oxidative phosphorylation protein complex expression in mouse brain and assays of mitochondrial function in engineered cell lines, which revealed a lack of metabolic flexibility and a contribution of the 3q29 gene PAK2. Together, these data indicate that metabolic disruption is associated with 3q29Del and is conserved across species.
    DOI:  https://doi.org/10.1126/sciadv.adh0558
  26. Nat Commun. 2023 Aug 18. 14(1): 5021
    Early-adulthood spike in protein translation drives aging via juvenile hormone/germline signaling.
    Harper S Kim, Danitra J Parker, Madison M Hardiman, Erin Munkácsy, Nisi Jiang, Aric N Rogers, Yidong Bai, Colin Brent, James A Mobley, Steven N Austad, Andrew M Pickering.
      Protein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age-related functional decline via juvenile hormone-lipid transfer protein axis and germline signaling. Our findings suggest that PT is adaptively suppressed after early-adulthood, alleviating later-life proteostatic burden, slowing down age-related functional decline, and improving lifespan. Our work provides a theoretical framework for understanding how lifetime PT dynamics shape future aging trajectories.
    DOI:  https://doi.org/10.1038/s41467-023-40618-x
  27. Nat Commun. 2023 Aug 18. 14(1): 5016
    TIGIT can inhibit T cell activation via ligation-induced nanoclusters, independent of CD226 co-stimulation.
    Jonathan D Worboys, Katherine N Vowell, Roseanna K Hare, Ashley R Ambrose, Margherita Bertuzzi, Michael A Conner, Florence P Patel, William H Zammit, Judit Gali-Moya, Khodor S Hazime, Katherine L Jones, Camille Rey, Stipan Jonjic, Tihana Lenac Rovis, Gillian M Tannahill, Gabriela Dos Santos Cruz De Matos, Jeremy D Waight, Daniel M Davis.
      TIGIT is an inhibitory receptor expressed on lymphocytes and can inhibit T cells by preventing CD226 co-stimulation through interactions in cis or through competition of shared ligands. Whether TIGIT directly delivers cell-intrinsic inhibitory signals in T cells remains unclear. Here we show, by analysing lymphocytes from matched human tumour and peripheral blood samples, that TIGIT and CD226 co-expression is rare on tumour-infiltrating lymphocytes. Using super-resolution microscopy and other techniques, we demonstrate that ligation with CD155 causes TIGIT to reorganise into dense nanoclusters, which coalesce with T cell receptor (TCR)-rich clusters at immune synapses. Functionally, this reduces cytokine secretion in a manner dependent on TIGIT's intracellular ITT-like signalling motif. Thus, we provide evidence that TIGIT directly inhibits lymphocyte activation, acting independently of CD226, requiring intracellular signalling that is proximal to the TCR. Within the subset of tumours where TIGIT-expressing cells do not commonly co-express CD226, this will likely be the dominant mechanism of action.
    DOI:  https://doi.org/10.1038/s41467-023-40755-3
  28. Nat Aging. 2023 Aug 16.
    Platelet factors are induced by longevity factor klotho and enhance cognition in young and aging mice.
    Cana Park, Oliver Hahn, Shweta Gupta, Arturo J Moreno, Francesca Marino, Blen Kedir, Dan Wang, Saul A Villeda, Tony Wyss-Coray, Dena B Dubal.
      Platelet factors regulate wound healing and can signal from the blood to the brain1,2. However, whether platelet factors modulate cognition, a highly valued and central manifestation of brain function, is unknown. Here we show that systemic platelet factor 4 (PF4) permeates the brain and enhances cognition. We found that, in mice, peripheral administration of klotho, a longevity and cognition-enhancing protein3-7, increased the levels of multiple platelet factors in plasma, including PF4. A pharmacologic intervention that inhibits platelet activation blocked klotho-mediated cognitive enhancement, indicating that klotho may require platelets to enhance cognition. To directly test the effects of platelet factors on the brain, we treated mice with vehicle or systemic PF4. In young mice, PF4 enhanced synaptic plasticity and cognition. In old mice, PF4 decreased cognitive deficits and restored aging-induced increases of select factors associated with cognitive performance in the hippocampus. The effects of klotho on cognition were still present in mice lacking PF4, suggesting this platelet factor is sufficient to enhance cognition but not necessary for the effects of klotho-and that other unidentified factors probably contribute. Augmenting platelet factors, possible messengers of klotho, may enhance cognition in the young brain and decrease cognitive deficits in the aging brain.
    DOI:  https://doi.org/10.1038/s43587-023-00468-0
  29. Nat Immunol. 2023 Aug 14.
    The road not taken en route to T cell exhaustion.
    Barsha Dash, Patrick G Hogan.
      
    DOI:  https://doi.org/10.1038/s41590-023-01596-w
  30. Science. 2023 Aug 18. 381(6659): eadd7564
    Yolk sac cell atlas reveals multiorgan functions during human early development.
    Issac Goh, Rachel A Botting, Antony Rose, Simone Webb, Justin Engelbert, Yorick Gitton, Emily Stephenson, Mariana Quiroga Londoño, Michael Mather, Nicole Mende, Ivan Imaz-Rosshandler, Lu Yang, Dave Horsfall, Daniela Basurto-Lozada, Nana-Jane Chipampe, Victoria Rook, Jimmy Tsz Hang Lee, Mai-Linh Ton, Daniel Keitley, Pavel Mazin, M S Vijayabaskar, Rebecca Hannah, Laure Gambardella, Kile Green, Stephane Ballereau, Megumi Inoue, Elizabeth Tuck, Valentina Lorenzi, Kwasi Kwakwa, Clara Alsinet, Bayanne Olabi, Mohi Miah, Chloe Admane, Dorin-Mirel Popescu, Meghan Acres, David Dixon, Thomas Ness, Rowen Coulthard, Steven Lisgo, Deborah J Henderson, Emma Dann, Chenqu Suo, Sarah J Kinston, Jong-Eun Park, Krzysztof Polanski, John Marioni, Stijn van Dongen, Kerstin B Meyer, Marella de Bruijn, James Palis, Sam Behjati, Elisa Laurenti, Nicola K Wilson, Roser Vento-Tormo, Alain Chédotal, Omer Bayraktar, Irene Roberts, Laura Jardine, Berthold Göttgens, Sarah A Teichmann, Muzlifah Haniffa.
      The extraembryonic yolk sac (YS) ensures delivery of nutritional support and oxygen to the developing embryo but remains ill-defined in humans. We therefore assembled a comprehensive multiomic reference of the human YS from 3 to 8 postconception weeks by integrating single-cell protein and gene expression data. Beyond its recognized role as a site of hematopoiesis, we highlight roles in metabolism, coagulation, vascular development, and hematopoietic regulation. We reconstructed the emergence and decline of YS hematopoietic stem and progenitor cells from hemogenic endothelium and revealed a YS-specific accelerated route to macrophage production that seeds developing organs. The multiorgan functions of the YS are superseded as intraembryonic organs develop, effecting a multifaceted relay of vital functions as pregnancy proceeds.
    DOI:  https://doi.org/10.1126/science.add7564
  31. Sci Transl Med. 2023 Aug 16. 15(709): eadd1951
    NKG2D-CAR T cells eliminate senescent cells in aged mice and nonhuman primates.
    Dong Yang, Bin Sun, Shirong Li, Wenwen Wei, Xiuyun Liu, Xiaoyue Cui, Xianning Zhang, Nan Liu, Lanzhen Yan, Yibin Deng, Xudong Zhao.
      Cellular senescence, characterized by stable cell cycle arrest, plays an important role in aging and age-associated pathologies. Eliminating senescent cells rejuvenates aged tissues and ameliorates age-associated diseases. Here, we identified that natural killer group 2 member D ligands (NKG2DLs) are up-regulated in senescent cells in vitro, regardless of stimuli that induced cellular senescence, and in various tissues of aged mice and nonhuman primates in vivo. Accordingly, we developed and demonstrated that chimeric antigen receptor (CAR) T cells targeting human NKG2DLs selectively and effectively diminish human cells undergoing senescence induced by oncogenic stress, replicative stress, DNA damage, or P16INK4a overexpression in vitro. Targeting senescent cells with mouse NKG2D-CAR T cells alleviated multiple aging-associated pathologies and improved physical performance in both irradiated and aged mice. Autologous T cells armed with the human NKG2D CAR effectively delete naturally occurring senescent cells in aged nonhuman primates without any observed adverse effects. Our findings establish that NKG2D-CAR T cells could serve as potent and selective senolytic agents for aging and age-associated diseases driven by senescence.
    DOI:  https://doi.org/10.1126/scitranslmed.add1951
  32. Nat Commun. 2023 Aug 14. 14(1): 4645
    GATA2 mitotic bookmarking is required for definitive haematopoiesis.
    Rita Silvério-Alves, Ilia Kurochkin, Anna Rydström, Camila Vazquez Echegaray, Jakob Haider, Matthew Nicholls, Christina Rode, Louise Thelaus, Aida Yifter Lindgren, Alexandra Gabriela Ferreira, Rafael Brandão, Jonas Larsson, Marella F T R de Bruijn, Javier Martin-Gonzalez, Carlos-Filipe Pereira.
      In mitosis, most transcription factors detach from chromatin, but some are retained and bookmark genomic sites. Mitotic bookmarking has been implicated in lineage inheritance, pluripotency and reprogramming. However, the biological significance of this mechanism in vivo remains unclear. Here, we address mitotic retention of the hemogenic factors GATA2, GFI1B and FOS during haematopoietic specification. We show that GATA2 remains bound to chromatin throughout mitosis, in contrast to GFI1B and FOS, via C-terminal zinc finger-mediated DNA binding. GATA2 bookmarks a subset of its interphase targets that are co-enriched for RUNX1 and other regulators of definitive haematopoiesis. Remarkably, homozygous mice harbouring the cyclin B1 mitosis degradation domain upstream Gata2 partially phenocopy knockout mice. Degradation of GATA2 at mitotic exit abolishes definitive haematopoiesis at aorta-gonad-mesonephros, placenta and foetal liver, but does not impair yolk sac haematopoiesis. Our findings implicate GATA2-mediated mitotic bookmarking as critical for definitive haematopoiesis and highlight a dependency on bookmarkers for lineage commitment.
    DOI:  https://doi.org/10.1038/s41467-023-40391-x
  33. Nature. 2023 Aug 16.
    Brain mitochondria predict a mouse's stress level.
      
    Keywords:  Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-02575-9
  34. Nat Genet. 2023 Aug 17.
    Genetic insights into human cortical organization and development through genome-wide analyses of 2,347 neuroimaging phenotypes.
    Varun Warrier, Eva-Maria Stauffer, Qin Qin Huang, Emilie M Wigdor, Eric A W Slob, Jakob Seidlitz, Lisa Ronan, Sofie L Valk, Travis T Mallard, Andrew D Grotzinger, Rafael Romero-Garcia, Simon Baron-Cohen, Daniel H Geschwind, Madeline A Lancaster, Graham K Murray, Michael J Gandal, Aaron Alexander-Bloch, Hyejung Won, Hilary C Martin, Edward T Bullmore, Richard A I Bethlehem.
      Our understanding of the genetics of the human cerebral cortex is limited both in terms of the diversity and the anatomical granularity of brain structural phenotypes. Here we conducted a genome-wide association meta-analysis of 13 structural and diffusion magnetic resonance imaging-derived cortical phenotypes, measured globally and at 180 bilaterally averaged regions in 36,663 individuals and identified 4,349 experiment-wide significant loci. These phenotypes include cortical thickness, surface area, gray matter volume, measures of folding, neurite density and water diffusion. We identified four genetic latent structures and causal relationships between surface area and some measures of cortical folding. These latent structures partly relate to different underlying gene expression trajectories during development and are enriched for different cell types. We also identified differential enrichment for neurodevelopmental and constrained genes and demonstrate that common genetic variants associated with cortical expansion are associated with cephalic disorders. Finally, we identified complex interphenotype and inter-regional genetic relationships among the 13 phenotypes, reflecting the developmental differences among them. Together, these analyses identify distinct genetic organizational principles of the cortex and their correlates with neurodevelopment.
    DOI:  https://doi.org/10.1038/s41588-023-01475-y
  35. Nat Commun. 2023 Aug 17. 14(1): 4999
    Single-cell genomics improves the discovery of risk variants and genes of atrial fibrillation.
    Alan Selewa, Kaixuan Luo, Michael Wasney, Linsin Smith, Xiaotong Sun, Chenwei Tang, Heather Eckart, Ivan P Moskowitz, Anindita Basu, Xin He, Sebastian Pott.
      Genome-wide association studies (GWAS) have linked hundreds of loci to cardiac diseases. However, in most loci the causal variants and their target genes remain unknown. We developed a combined experimental and analytical approach that integrates single cell epigenomics with GWAS to prioritize risk variants and genes. We profiled accessible chromatin in single cells obtained from human hearts and leveraged the data to study genetics of Atrial Fibrillation (AF), the most common cardiac arrhythmia. Enrichment analysis of AF risk variants using cell-type-resolved open chromatin regions (OCRs) implicated cardiomyocytes as the main mediator of AF risk. We then performed statistical fine-mapping, leveraging the information in OCRs, and identified putative causal variants in 122 AF-associated loci. Taking advantage of the fine-mapping results, our novel statistical procedure for gene discovery prioritized 46 high-confidence risk genes, highlighting transcription factors and signal transduction pathways important for heart development. In summary, our analysis provides a comprehensive map of AF risk variants and genes, and a general framework to integrate single-cell genomics with genetic studies of complex traits.
    DOI:  https://doi.org/10.1038/s41467-023-40505-5
  36. Nat Commun. 2023 Aug 18. 14(1): 5027
    A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer's disease mouse model.
    Andrew E Warfield, Pooja Gupta, Madison M Ruhmann, Quiana L Jeffs, Genevieve C Guidone, Hannah W Rhymes, McKenzi I Thompson, William D Todd.
      Alzheimer's disease (AD) patients exhibit progressive disruption of entrained circadian rhythms and an aberrant circadian input pathway may underlie such dysfunction. Here we examine AD-related pathology and circadian dysfunction in the APPSwe-Tau (TAPP) model of AD. We show these mice exhibit phase delayed body temperature and locomotor activity with increases around the active-to-rest phase transition. Similar AD-related disruptions are associated with sundowning, characterized by late afternoon and early evening agitation and aggression, and we show TAPP mice exhibit increased aggression around this transition. We show such circadian dysfunction and aggression coincide with hyperphosphorylated Tau (pTau) development in lateral parabrachial (LPB) neurons, with these disturbances appearing earlier in females. Finally, we show LPB neurons, including those expressing dynorphin (LPBdyn), project to circadian structures and are affected by pTau, and LPBdyn ablations partially recapitulate the hyperthermia of TAPP mice. Altogether we link pTau in a brainstem circadian input pathway to AD-related disturbances relevant to sundowning.
    DOI:  https://doi.org/10.1038/s41467-023-40546-w
  37. Nat Cell Biol. 2023 Aug 17.
    Lipid saturation controls nuclear envelope function.
    Anete Romanauska, Alwin Köhler.
      The nuclear envelope (NE) is a spherical double membrane with elastic properties. How NE shape and elasticity are regulated by lipid chemistry is unknown. Here we discover lipid acyl chain unsaturation as essential for NE and nuclear pore complex (NPC) architecture and function. Increased lipid saturation rigidifies the NE and the endoplasmic reticulum into planar, polygonal membranes, which are fracture prone. These membranes exhibit a micron-scale segregation of lipids into ordered and disordered phases, excluding NPCs from the ordered phase. Balanced lipid saturation is required for NPC integrity, pore membrane curvature and nucleocytoplasmic transport. Oxygen deprivation amplifies the impact of saturated lipids, causing NE rigidification and rupture. Conversely, lipid droplets buffer saturated lipids to preserve NE architecture. Our study uncovers a fundamental link between lipid acyl chain structure and the integrity of the cell nucleus with implications for nuclear membrane malfunction in ischaemic tissues.
    DOI:  https://doi.org/10.1038/s41556-023-01207-8
  38. Nat Ecol Evol. 2023 Aug 17.
    A genetic history of continuity and mobility in the Iron Age central Mediterranean.
    Hannah M Moots, Margaret Antonio, Susanna Sawyer, Jeffrey P Spence, Victoria Oberreiter, Clemens L Weiß, Michaela Lucci, Yahia Mehdi Seddik Cherifi, Francesco La Pastina, Francesco Genchi, Elisa Praxmeier, Brina Zagorc, Olivia Cheronet, Kadir T Özdoğan, Lea Demetz, Selma Amrani, Francesca Candilio, Daniela De Angelis, Gabriella Gasperetti, Daniel Fernandes, Ziyue Gao, Mounir Fantar, Alfredo Coppa, Jonathan K Pritchard, Ron Pinhasi.
      The Iron Age was a dynamic period in central Mediterranean history, with the expansion of Greek and Phoenician colonies and the growth of Carthage into the dominant maritime power of the Mediterranean. These events were facilitated by the ease of long-distance travel following major advances in seafaring. We know from the archaeological record that trade goods and materials were moving across great distances in unprecedented quantities, but it is unclear how these patterns correlate with human mobility. Here, to investigate population mobility and interactions directly, we sequenced the genomes of 30 ancient individuals from coastal cities around the central Mediterranean, in Tunisia, Sardinia and central Italy. We observe a meaningful contribution of autochthonous populations, as well as highly heterogeneous ancestry including many individuals with non-local ancestries from other parts of the Mediterranean region. These results highlight both the role of local populations and the extreme interconnectedness of populations in the Iron Age Mediterranean. By studying these trans-Mediterranean neighbours together, we explore the complex interplay between local continuity and mobility that shaped the Iron Age societies of the central Mediterranean.
    DOI:  https://doi.org/10.1038/s41559-023-02143-4
  39. Nat Commun. 2023 Aug 12. 14(1): 4873
    SnapFISH: a computational pipeline to identify chromatin loops from multiplexed DNA FISH data.
    Lindsay Lee, Hongyu Yu, Bojing Blair Jia, Adam Jussila, Chenxu Zhu, Jiawen Chen, Liangqi Xie, Antonina Hafner, Shreya Mishra, Duan Dennis Wang, Caterina Strambio-De-Castillia, Alistair Boettiger, Bing Ren, Yun Li, Ming Hu.
      Multiplexed DNA fluorescence in situ hybridization (FISH) imaging technologies have been developed to map the folding of chromatin fibers at tens of nanometers and up to several kilobases in resolution in single cells. However, computational methods to reliably identify chromatin loops from such imaging datasets are still lacking. Here we present a Single-Nucleus Analysis Pipeline for multiplexed DNA FISH (SnapFISH), to process the multiplexed DNA FISH data and identify chromatin loops. SnapFISH can identify known chromatin loops from mouse embryonic stem cells with high sensitivity and accuracy. In addition, SnapFISH obtains comparable results of chromatin loops across datasets generated from diverse imaging technologies. SnapFISH is freely available at https://github.com/HuMingLab/SnapFISH .
    DOI:  https://doi.org/10.1038/s41467-023-40658-3
  40. Nat Commun. 2023 Aug 14. 14(1): 4895
    Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen.
    Chinaemerem U Onyishi, Guillaume E Desanti, Alex L Wilkinson, Samuel Lara-Reyna, Eva-Maria Frickel, Gyorgy Fejer, Olivier D Christophe, Clare E Bryant, Subhankar Mukhopadhyay, Siamon Gordon, Robin C May.
      The opportunistic fungal pathogen Cryptococcus neoformans causes lethal infections in immunocompromised patients. Macrophages are central to the host response to cryptococci; however, it is unclear how C. neoformans is recognised and phagocytosed by macrophages. Here we investigate the role of TLR4 in the non-opsonic phagocytosis of C. neoformans. We find that loss of TLR4 function unexpectedly increases phagocytosis of non-opsonised cryptococci by murine and human macrophages. The increased phagocytosis observed in Tlr4-/- cells was dampened by pre-treatment of macrophages with oxidised-LDL, a known ligand of scavenger receptors. The scavenger receptor, macrophage scavenger receptor 1 (MSR1) (also known as SR-A1 or CD204) was upregulated in Tlr4-/- macrophages. Genetic ablation of MSR1 resulted in a 75% decrease in phagocytosis of non-opsonised cryptococci, strongly suggesting that it is a key non-opsonic receptor for this pathogen. We go on to show that MSR1-mediated uptake likely involves the formation of a multimolecular signalling complex involving FcγR leading to SYK, PI3K, p38 and ERK1/2 activation to drive actin remodelling and phagocytosis. Altogether, our data indicate a hitherto unidentified role for TLR4/MSR1 crosstalk in the non-opsonic phagocytosis of C. neoformans.
    DOI:  https://doi.org/10.1038/s41467-023-40635-w
  41. Nat Commun. 2023 Aug 15. 14(1): 4933
    Subtle adversarial image manipulations influence both human and machine perception.
    Vijay Veerabadran, Josh Goldman, Shreya Shankar, Brian Cheung, Nicolas Papernot, Alexey Kurakin, Ian Goodfellow, Jonathon Shlens, Jascha Sohl-Dickstein, Michael C Mozer, Gamaleldin F Elsayed.
      Although artificial neural networks (ANNs) were inspired by the brain, ANNs exhibit a brittleness not generally observed in human perception. One shortcoming of ANNs is their susceptibility to adversarial perturbations-subtle modulations of natural images that result in changes to classification decisions, such as confidently mislabelling an image of an elephant, initially classified correctly, as a clock. In contrast, a human observer might well dismiss the perturbations as an innocuous imaging artifact. This phenomenon may point to a fundamental difference between human and machine perception, but it drives one to ask whether human sensitivity to adversarial perturbations might be revealed with appropriate behavioral measures. Here, we find that adversarial perturbations that fool ANNs similarly bias human choice. We further show that the effect is more likely driven by higher-order statistics of natural images to which both humans and ANNs are sensitive, rather than by the detailed architecture of the ANN.
    DOI:  https://doi.org/10.1038/s41467-023-40499-0
  42. Nat Cell Biol. 2023 Aug 14.
    Balancing lysosome abundance in health and disease.
    Anders P Mutvei, Michal J Nagiec, John Blenis.
      Lysosomes are catabolic organelles that govern numerous cellular processes, including macromolecule degradation, nutrient signalling and ion homeostasis. Aberrant changes in lysosome abundance are implicated in human diseases. Here we outline the mechanisms of lysosome biogenesis and turnover, and discuss how changes in the lysosome pool impact physiological and pathophysiological processes.
    DOI:  https://doi.org/10.1038/s41556-023-01197-7
  43. Cell Stem Cell. 2023 Aug 09. pii: S1934-5909(23)00257-6. [Epub ahead of print]
    Single-cell multi-omics defines the cell-type-specific impact of splicing aberrations in human hematopoietic clonal outgrowths.
    Mariela Cortés-López, Paulina Chamely, Allegra G Hawkins, Robert F Stanley, Ariel D Swett, Saravanan Ganesan, Tarek H Mouhieddine, Xiaoguang Dai, Lloyd Kluegel, Celine Chen, Kiran Batta, Nili Furer, Rahul S Vedula, John Beaulaurier, Alexander W Drong, Scott Hickey, Neville Dusaj, Gavriel Mullokandov, Adam M Stasiw, Jiayu Su, Ronan Chaligné, Sissel Juul, Eoghan Harrington, David A Knowles, Catherine J Potenski, Daniel H Wiseman, Amos Tanay, Liran Shlush, Robert C Lindsley, Irene M Ghobrial, Justin Taylor, Omar Abdel-Wahab, Federico Gaiti, Dan A Landau.
      RNA splicing factors are recurrently mutated in clonal blood disorders, but the impact of dysregulated splicing in hematopoiesis remains unclear. To overcome technical limitations, we integrated genotyping of transcriptomes (GoT) with long-read single-cell transcriptomics and proteogenomics for single-cell profiling of transcriptomes, surface proteins, somatic mutations, and RNA splicing (GoT-Splice). We applied GoT-Splice to hematopoietic progenitors from myelodysplastic syndrome (MDS) patients with mutations in the core splicing factor SF3B1. SF3B1mut cells were enriched in the megakaryocytic-erythroid lineage, with expansion of SF3B1mut erythroid progenitor cells. We uncovered distinct cryptic 3' splice site usage in different progenitor populations and stage-specific aberrant splicing during erythroid differentiation. Profiling SF3B1-mutated clonal hematopoiesis samples revealed that erythroid bias and cell-type-specific cryptic 3' splice site usage in SF3B1mut cells precede overt MDS. Collectively, GoT-Splice defines the cell-type-specific impact of somatic mutations on RNA splicing, from early clonal outgrowths to overt neoplasia, directly in human samples.
    Keywords:  BAX; RNA-seq; SF3B1; clonal hematopoiesis; genotyping; long-read sequencing; multi-omics; myelodysplastic syndrome; single cell; splicing
    DOI:  https://doi.org/10.1016/j.stem.2023.07.012
  44. Nat Commun. 2023 Aug 15. 14(1): 4831
    Quantitative real-time in-cell imaging reveals heterogeneous clusters of proteins prior to condensation.
    Chenyang Lan, Juhyeong Kim, Svenja Ulferts, Fernando Aprile-Garcia, Sophie Weyrauch, Abhinaya Anandamurugan, Robert Grosse, Ritwick Sawarkar, Aleks Reinhardt, Thorsten Hugel.
      Our current understanding of biomolecular condensate formation is largely based on observing the final near-equilibrium condensate state. Despite expectations from classical nucleation theory, pre-critical protein clusters were recently shown to form under subsaturation conditions in vitro; if similar long-lived clusters comprising more than a few molecules are also present in cells, our understanding of the physical basis of biological phase separation may fundamentally change. Here, we combine fluorescence microscopy with photobleaching analysis to quantify the formation of clusters of NELF proteins in living, stressed cells. We categorise small and large clusters based on their dynamics and their response to p38 kinase inhibition. We find a broad distribution of pre-condensate cluster sizes and show that NELF protein cluster formation can be explained as non-classical nucleation with a surprisingly flat free-energy landscape for a wide range of sizes and an inhibition of condensation in unstressed cells.
    DOI:  https://doi.org/10.1038/s41467-023-40540-2
  45. Nat Cardiovasc Res. 2023 Apr;2(4): 399-416
    Defining cardiac functional recovery in end-stage heart failure at single-cell resolution.
    Junedh M Amrute, Lulu Lai, Pan Ma, Andrew L Koenig, Kenji Kamimoto, Andrea Bredemeyer, Thirupura S Shankar, Christoph Kuppe, Farid F Kadyrov, Linda J Schulte, Dylan Stoutenburg, Benjamin J Kopecky, Sutip Navankasattusas, Joseph Visker, Samantha A Morris, Rafael Kramann, Florian Leuschner, Douglas L Mann, Stavros G Drakos, Kory J Lavine.
      Recovery of cardiac function is the holy grail of heart failure therapy yet is infrequently observed and remains poorly understood. In this study, we performed single-nucleus RNA sequencing from patients with heart failure who recovered left ventricular systolic function after left ventricular assist device implantation, patients who did not recover and non-diseased donors. We identified cell-specific transcriptional signatures of recovery, most prominently in macrophages and fibroblasts. Within these cell types, inflammatory signatures were negative predictors of recovery, and downregulation of RUNX1 was associated with recovery. In silico perturbation of RUNX1 in macrophages and fibroblasts recapitulated the transcriptional state of recovery. Cardiac recovery mediated by BET inhibition in mice led to decreased macrophage and fibroblast Runx1 expression and diminished chromatin accessibility within a Runx1 intronic peak and acquisition of human recovery signatures. These findings suggest that cardiac recovery is a unique biological state and identify RUNX1 as a possible therapeutic target to facilitate cardiac recovery.
    DOI:  https://doi.org/10.1038/s44161-023-00260-8
  46. FASEB J. 2023 09;37(9): e23140
    HIF-1α inhibition in macrophages preserves acute liver failure by reducing IL-1β production.
    Xiangrong Kong, Wei Liu, Xinwen Zhang, Chendong Zhou, Xinyu Sun, Long Cheng, Jinxia Lin, Zhifu Xie, Jingya Li.
      The development of acute liver failure (ALF) is dependent on its local inducer. Inflammation is a high-frequency and critical factor that accelerates hepatocyte death and liver failure. In response to injury stress, the expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages is promoted by both oxygen-dependent and oxygen-independent mechanisms, thus promoting the expression and secretion of the cytokine interleukin-1β (IL-1β). IL-1β further induces hepatocyte apoptosis or necrosis by signaling through the receptor (IL-1R) on hepatocyte. HIF-1α knockout in macrophages or IL-1R knockout in hepatocytes protects against liver failure. However, whether HIF-1α inhibition in macrophages has a protective role in ALF is unclear. In this study, we revealed that the small molecule HIF-1α inhibitor PX-478 inhibits the expression and secretion of IL-1β, but not tumor necrosis factor α (TNFα), in bone marrow-derived macrophages (BMDMs). PX-478 pretreatment alleviates liver injury in LPS/D-GalN-induced ALF mice by decreasing the hepatic inflammatory response. In addition, preventive or therapeutic administration of PX-478 combined with TNFα neutralizing antibody markedly improved LPS/D-GalN-induced ALF. Taken together, our data suggest that PX-478 administration leads to HIF-1α inhibition and decreased IL-1β secretion in macrophages, which represents a promising therapeutic strategy for inflammation-induced ALF.
    Keywords:  HIF-1α inhibitor; acute liver failure; cell death; interleukin-1β; macrophage
    DOI:  https://doi.org/10.1096/fj.202300428RR
  47. Cell. 2023 Aug 17. pii: S0092-8674(23)00803-6. [Epub ahead of print]186(17): 3524-3526
    The calvaria stands alone: Unique aspects of the skull bone marrow-meninges border.
    Sachin P Gadani, Peter A Calabresi.
      Channels connecting the skull bone marrow and the meninges have recently been discovered as a path for immune cell and molecule trafficking. In this issue of Cell, Kolabas, Kuemmerle, Perneczky, Förstera, and colleagues characterize these channels in humans and mice, revealing unique features of skull bone marrow and localized activation in human pathology.
    DOI:  https://doi.org/10.1016/j.cell.2023.07.025
  48. Nature. 2023 Aug 16.
    Older mouse brains rejuvenated by protein found in young blood.
    Saima May Sidik.
      
    DOI:  https://doi.org/10.1038/d41586-023-02563-z
  49. Nat Immunol. 2023 Aug 14.
    Single-cell multiomic analysis of thymocyte development reveals drivers of CD4+ T cell and CD8+ T cell lineage commitment.
    Zoë Steier, Dominik A Aylard, Laura L McIntyre, Isabel Baldwin, Esther Jeong Yoon Kim, Lydia K Lutes, Can Ergen, Tse-Shun Huang, Ellen A Robey, Nir Yosef, Aaron Streets.
      The development of CD4+ T cells and CD8+ T cells in the thymus is critical to adaptive immunity and is widely studied as a model of lineage commitment. Recognition of self-peptide major histocompatibility complex (MHC) class I or II by the T cell antigen receptor (TCR) determines the CD8+ or CD4+ T cell lineage choice, respectively, but how distinct TCR signals drive transcriptional programs of lineage commitment remains largely unknown. Here we applied CITE-seq to measure RNA and surface proteins in thymocytes from wild-type and T cell lineage-restricted mice to generate a comprehensive timeline of cell states for each T cell lineage. These analyses identified a sequential process whereby all thymocytes initiate CD4+ T cell lineage differentiation during a first wave of TCR signaling, followed by a second TCR signaling wave that coincides with CD8+ T cell lineage specification. CITE-seq and pharmaceutical inhibition experiments implicated a TCR-calcineurin-NFAT-GATA3 axis in driving the CD4+ T cell fate. Our data provide a resource for understanding cell fate decisions and implicate a sequential selection process in guiding lineage choice.
    DOI:  https://doi.org/10.1038/s41590-023-01584-0
  50. Nat Commun. 2023 Aug 17. 14(1): 4991
    An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress.
    Taichi Igarashi, Marianne Mazevet, Takaaki Yasuhara, Kimiyoshi Yano, Akifumi Mochizuki, Makoto Nishino, Tatsuya Yoshida, Yukihiro Yoshida, Nobuhiko Takamatsu, Akihide Yoshimi, Kouya Shiraishi, Hidehito Horinouchi, Takashi Kohno, Ryuji Hamamoto, Jun Adachi, Lee Zou, Bunsyo Shiotani.
      Activation of the KRAS oncogene is a source of replication stress, but how this stress is generated and how it is tolerated by cancer cells remain poorly understood. Here we show that induction of KRASG12V expression in untransformed cells triggers H3K27me3 and HP1-associated chromatin compaction in an RNA transcription dependent manner, resulting in replication fork slowing and cell death. Furthermore, elevated ATR expression is necessary and sufficient for tolerance of KRASG12V-induced replication stress to expand replication stress-tolerant cells (RSTCs). PrimPol is phosphorylated at Ser255, a potential Chk1 substrate site, under KRASG12V-induced replication stress and promotes repriming to maintain fork progression and cell survival in an ATR/Chk1-dependent manner. However, ssDNA gaps are generated at heterochromatin by PrimPol-dependent repriming, leading to genomic instability. These results reveal a role of ATR-PrimPol in enabling precancerous cells to survive KRAS-induced replication stress and expand clonally with accumulation of genomic instability.
    DOI:  https://doi.org/10.1038/s41467-023-40578-2
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