bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–05–26
thirty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.
  2. Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements.
  3. Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation.
  4. Brain cell-type shifts in Alzheimer's disease, autism, and schizophrenia interrogated using methylomics and genetics.
  5. SnapShot: Cell size control.
  6. Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis.
  7. Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies.
  8. Enhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys.
  9. Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis.
  10. Software tools identify forgotten genes.
  11. These crows have counting skills previously only seen in people.
  12. Fluorescent fatty acid conjugates for live cell imaging of peroxisomes.
  13. Mitochondria at the crossroads of health and disease.
  14. Severe infections as a gateway to dementia.
  15. Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance.
  16. Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.
  17. Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice.
  18. Production of deoxycholic acid by low-abundant microbial species is associated with impaired glucose metabolism.
  19. Single molecule delivery into living cells.
  20. SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
  21. Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia.
  22. Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.
  23. An emerging target for male contraception.
  24. Genome-wide Cas9-mediated screening of essential non-coding regulatory elements via libraries of paired single-guide RNAs.
  25. Natural proteome diversity links aneuploidy tolerance to protein turnover.
  26. A nutrient responsive lipase mediates gut-brain communication to regulate insulin secretion in Drosophila.
  27. Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.
  28. Illuminating mitochondrial translation through mouse models.
  29. Single-cell genomics and regulatory networks for 388 human brains.
  30. Transcriptomic and spatial dissection of human ex vivo right atrial tissue reveals proinflammatory microvascular changes in ischemic heart disease.
  31. Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms.
  32. Integrating single cell expression quantitative trait loci summary statistics to understand complex trait risk genes.
  1. Nat Commun. 2024 May 21. 15(1): 4325
    Cell of origin epigenetic priming determines susceptibility to Tet2 mutation.
    Giulia Schiroli, Vinay Kartha, Fabiana M Duarte, Trine A Kristiansen, Christina Mayerhofer, Rojesh Shrestha, Andrew Earl, Yan Hu, Tristan Tay, Catherine Rhee, Jason D Buenrostro, David T Scadden.
      Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigate how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we find that the epigenetic features of clones at similar differentiation status are highly heterogeneous and functionally respond differently to Tet2 mutation. Cell differentiation stage also influences Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitizes cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.
    DOI:  https://doi.org/10.1038/s41467-024-48508-6
  2. Sci Adv. 2024 May 24. 10(21): eadj4452
    Using a comprehensive atlas and predictive models to reveal the complexity and evolution of brain-active regulatory elements.
    Henry E Pratt, Gregory Andrews, Nicole Shedd, Nishigandha Phalke, Tongxin Li, Anusri Pampari, Matthew Jensen, Cindy Wen, PsychENCODE Consortium, Michael J Gandal, Daniel H Geschwind, Mark Gerstein, Jill Moore, Anshul Kundaje, Andrés Colubri, Zhiping Weng.
      Most genetic variants associated with psychiatric disorders are located in noncoding regions of the genome. To investigate their functional implications, we integrate epigenetic data from the PsychENCODE Consortium and other published sources to construct a comprehensive atlas of candidate brain cis-regulatory elements. Using deep learning, we model these elements' sequence syntax and predict how binding sites for lineage-specific transcription factors contribute to cell type-specific gene regulation in various types of glia and neurons. The elements' evolutionary history suggests that new regulatory information in the brain emerges primarily via smaller sequence mutations within conserved mammalian elements rather than entirely new human- or primate-specific sequences. However, primate-specific candidate elements, particularly those active during fetal brain development and in excitatory neurons and astrocytes, are implicated in the heritability of brain-related human traits. Additionally, we introduce PsychSCREEN, a web-based platform offering interactive visualization of PsychENCODE-generated genetic and epigenetic data from diverse brain cell types in individuals with psychiatric disorders and healthy controls.
    DOI:  https://doi.org/10.1126/sciadv.adj4452
  3. Immunity. 2024 May 14. pii: S1074-7613(24)00227-9. [Epub ahead of print]
    Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation.
    Ipsita Subudhi, Piotr Konieczny, Aleksandr Prystupa, Rochelle L Castillo, Erica Sze-Tu, Yue Xing, Daniel Rosenblum, Ilana Reznikov, Ikjot Sidhu, Cynthia Loomis, Catherine P Lu, Niroshana Anandasabapathy, Mayte Suárez-Fariñas, Johann E Gudjonsson, Aristotelis Tsirigos, Jose U Scher, Shruti Naik.
      Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.
    Keywords:  HIF1α; epithelium; glycolysis; inflammation; lactate; metabolism; skin; type 17 cells
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.022
  4. Sci Adv. 2024 May 24. 10(21): eadn7655
    Brain cell-type shifts in Alzheimer's disease, autism, and schizophrenia interrogated using methylomics and genetics.
    Chloe X Yap, Daniel D Vo, Matthew G Heffel, Arjun Bhattacharya, Cindy Wen, Yuanhao Yang, Kathryn E Kemper, Jian Zeng, Zhili Zheng, Zhihong Zhu, Eilis Hannon, Dorothea Seiler Vellame, Alice Franklin, Christa Caggiano, Brie Wamsley, Daniel H Geschwind, Noah Zaitlen, Alexander Gusev, Bogdan Pasaniuc, Jonathan Mill, Chongyuan Luo, Michael J Gandal.
      Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial cell loss contributes to Alzheimer's disease, with comparable effect size to APOE genotype among older people. Genome-wide association identified five genetic loci related to cell-type composition, involving plausible genes for the neurovascular unit (P2RX5 and TRPV3) and excitatory neurons (DPY30 and MEMO1). These results implicate specific cell-type shifts in the pathophysiology of neuropsychiatric disorders.
    DOI:  https://doi.org/10.1126/sciadv.adn7655
  5. Cell. 2024 May 23. pii: S0092-8674(24)00456-2. [Epub ahead of print]187(11): 2896-2896.e1
    SnapShot: Cell size control.
    Bruce Futcher, Douglas R Kellogg.
      Cell size exhibits remarkable diversity across and within organisms. Size variation correlates with DNA content and growth rates and is regulated by complex models of cell size control that are yet to be mechanistically defined. To view this SnapShot, open or download the PDF.
    DOI:  https://doi.org/10.1016/j.cell.2024.04.030
  6. Nat Commun. 2024 May 18. 15(1): 4232
    Tlr9 deficiency in B cells leads to obesity by promoting inflammation and gut dysbiosis.
    Pai Wang, Xin Yang, Luyao Zhang, Sha Sha, Juan Huang, Jian Peng, Jianlei Gu, James Alexander Pearson, Youjia Hu, Hongyu Zhao, F Susan Wong, Quan Wang, Li Wen.
      Toll-like receptor 9 (TLR9) recognizes bacterial, viral and self DNA and play an important role in immunity and inflammation. However, the role of TLR9 in obesity is less well-studied. Here, we generate B-cell-specific Tlr9-deficient (Tlr9fl/fl/Cd19Cre+/-, KO) B6 mice and model obesity using a high-fat diet. Compared with control mice, B-cell-specific-Tlr9-deficient mice exhibited increased fat tissue inflammation, weight gain, and impaired glucose and insulin tolerance. Furthermore, the frequencies of IL-10-producing-B cells and marginal zone B cells were reduced, and those of follicular and germinal center B cells were increased. This was associated with increased frequencies of IFNγ-producing-T cells and increased follicular helper cells. In addition, gut microbiota from the KO mice induced a pro-inflammatory state leading to immunological and metabolic dysregulation when transferred to germ-free mice. Using 16 S rRNA gene sequencing, we identify altered gut microbial communities including reduced Lachnospiraceae, which may play a role in altered metabolism in KO mice. We identify an important network involving Tlr9, Irf4 and Il-10 interconnecting metabolic homeostasis, with the function of B and T cells, and gut microbiota in obesity.
    DOI:  https://doi.org/10.1038/s41467-024-48611-8
  7. Nat Commun. 2024 May 24. 15(1): 4444
    Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies.
    Meng-Han Wu, Felipe Valenca-Pereira, Francesca Cendali, Emily L Giddings, Catherine Pham-Danis, Michael C Yarnell, Amanda J Novak, Tonya M Brunetti, Scott B Thompson, Jorge Henao-Mejia, Richard A Flavell, Angelo D'Alessandro, M Eric Kohler, Mercedes Rincon.
      Mitochondrial respiration is essential for the survival and function of T cells used in adoptive cellular therapies. However, strategies that specifically enhance mitochondrial respiration to promote T cell function remain limited. Here, we investigate methylation-controlled J protein (MCJ), an endogenous negative regulator of mitochondrial complex I expressed in CD8 cells, as a target for improving the efficacy of adoptive T cell therapies. We demonstrate that MCJ inhibits mitochondrial respiration in murine CD8+ CAR-T cells and that deletion of MCJ increases their in vitro and in vivo efficacy against murine B cell leukaemia. Similarly, MCJ deletion in ovalbumin (OVA)-specific CD8+ T cells also increases their efficacy against established OVA-expressing melanoma tumors in vivo. Furthermore, we show for the first time that MCJ is expressed in human CD8 cells and that the level of MCJ expression correlates with the functional activity of CD8+ CAR-T cells. Silencing MCJ expression in human CD8 CAR-T cells increases their mitochondrial metabolism and enhances their anti-tumor activity. Thus, targeting MCJ may represent a potential therapeutic strategy to increase mitochondrial metabolism and improve the efficacy of adoptive T cell therapies.
    DOI:  https://doi.org/10.1038/s41467-024-48653-y
  8. Nat Commun. 2024 May 18. 15(1): 4247
    Enhancing in vivo cell and tissue targeting by modulation of polymer nanoparticles and macrophage decoys.
    Alexandra S Piotrowski-Daspit, Laura G Bracaglia, David A Eaton, Owen Richfield, Thomas C Binns, Claire Albert, Jared Gould, Ryland D Mortlock, Marie E Egan, Jordan S Pober, W Mark Saltzman.
      The in vivo efficacy of polymeric nanoparticles (NPs) is dependent on their pharmacokinetics, including time in circulation and tissue tropism. Here we explore the structure-function relationships guiding physiological fate of a library of poly(amine-co-ester) (PACE) NPs with different compositions and surface properties. We find that circulation half-life as well as tissue and cell-type tropism is dependent on polymer chemistry, vehicle characteristics, dosing, and strategic co-administration of distribution modifiers, suggesting that physiological fate can be optimized by adjusting these parameters. Our high-throughput quantitative microscopy-based platform to measure the concentration of nanomedicines in the blood combined with detailed biodistribution assessments and pharmacokinetic modeling provides valuable insight into the dynamic in vivo behavior of these polymer NPs. Our results suggest that PACE NPs-and perhaps other NPs-can be designed with tunable properties to achieve desired tissue tropism for the in vivo delivery of nucleic acid therapeutics. These findings can guide the rational design of more effective nucleic acid delivery vehicles for in vivo applications.
    DOI:  https://doi.org/10.1038/s41467-024-48442-7
  9. Nat Commun. 2024 May 21. 15(1): 4340
    Disruption of TIGAR-TAK1 alleviates immunopathology in a murine model of sepsis.
    Dongdong Wang, Yanxia Li, Hao Yang, Xiaoqi Shen, Xiaolin Shi, Chenyu Li, Yongjing Zhang, Xiaoyu Liu, Bin Jiang, Xudong Zhu, Hanwen Zhang, Xiaoyu Li, Hui Bai, Qing Yang, Wei Gao, Fang Bai, Yong Ji, Qi Chen, Jingjing Ben.
      Macrophage-orchestrated inflammation contributes to multiple diseases including sepsis. However, the underlying mechanisms remain to be defined clearly. Here, we show that macrophage TP53-induced glycolysis and apoptosis regulator (TIGAR) is up-regulated in murine sepsis models. When myeloid Tigar is ablated, sepsis induced by either lipopolysaccharide treatment or cecal ligation puncture in male mice is attenuated via inflammation inhibition. Mechanistic characterizations indicate that TIGAR directly binds to transforming growth factor β-activated kinase (TAK1) and promotes tumor necrosis factor receptor-associated factor 6-mediated ubiquitination and auto-phosphorylation of TAK1, in which residues 152-161 of TIGAR constitute crucial motif independent of its phosphatase activity. Interference with the binding of TIGAR to TAK1 by 5Z-7-oxozeaenol exhibits therapeutic effects in male murine model of sepsis. These findings demonstrate a non-canonical function of macrophage TIGAR in promoting inflammation, and confer a potential therapeutic target for sepsis by disruption of TIGAR-TAK1 interaction.
    DOI:  https://doi.org/10.1038/s41467-024-48708-0
  10. Nature. 2024 May 24.
    Software tools identify forgotten genes.
    Matthew Hutson.
      
    Keywords:  Genetics; Genomics; Technology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-024-01548-w
  11. Nature. 2024 May 23.
    These crows have counting skills previously only seen in people.
    Mariana Lenharo.
      
    Keywords:  Animal behaviour; Communication; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-01482-x
  12. Nat Commun. 2024 May 21. 15(1): 4314
    Fluorescent fatty acid conjugates for live cell imaging of peroxisomes.
    Daria Korotkova, Anya Borisyuk, Anthony Guihur, Manon Bardyn, Fabien Kuttler, Luc Reymond, Milena Schuhmacher, Triana Amen.
      Peroxisomes are eukaryotic organelles that are essential for multiple metabolic pathways, including fatty acid oxidation, degradation of amino acids, and biosynthesis of ether lipids. Consequently, peroxisome dysfunction leads to pediatric-onset neurodegenerative conditions, including Peroxisome Biogenesis Disorders (PBD). Due to the dynamic, tissue-specific, and context-dependent nature of their biogenesis and function, live cell imaging of peroxisomes is essential for studying peroxisome regulation, as well as for the diagnosis of PBD-linked abnormalities. However, the peroxisomal imaging toolkit is lacking in many respects, with no reporters for substrate import, nor cell-permeable probes that could stain dysfunctional peroxisomes. Here we report that the BODIPY-C12 fluorescent fatty acid probe stains functional and dysfunctional peroxisomes in live mammalian cells. We then go on to improve BODIPY-C12, generating peroxisome-specific reagents, PeroxiSPY650 and PeroxiSPY555. These probes combine high peroxisome specificity, bright fluorescence in the red and far-red spectrum, and fast non-cytotoxic staining, making them ideal tools for live cell, whole organism, or tissue imaging of peroxisomes. Finally, we demonstrate that PeroxiSPY enables diagnosis of peroxisome abnormalities in the PBD CRISPR/Cas9 cell models and patient-derived cell lines.
    DOI:  https://doi.org/10.1038/s41467-024-48679-2
  13. Cell. 2024 May 23. pii: S0092-8674(24)00463-X. [Epub ahead of print]187(11): 2601-2627
    Mitochondria at the crossroads of health and disease.
    Anu Suomalainen, Jodi Nunnari.
      Mitochondria reside at the crossroads of catabolic and anabolic metabolism-the essence of life. How their structure and function are dynamically tuned in response to tissue-specific needs for energy, growth repair, and renewal is being increasingly understood. Mitochondria respond to intrinsic and extrinsic stresses and can alter cell and organismal function by inducing metabolic signaling within cells and to distal cells and tissues. Here, we review how the centrality of mitochondrial functions manifests in health and a broad spectrum of diseases and aging.
    DOI:  https://doi.org/10.1016/j.cell.2024.04.037
  14. Nat Aging. 2024 May 23.
    Severe infections as a gateway to dementia.
    Mika Kivimäki, Keenan A Walker.
      
    DOI:  https://doi.org/10.1038/s43587-024-00643-x
  15. Immunity. 2024 May 14. pii: S1074-7613(24)00229-2. [Epub ahead of print]
    Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance.
    Jiping Sun, Youqin Zhang, Qingbing Zhang, Lin Hu, Linfeng Zhao, Hongdong Wang, Yue Yuan, Hongshen Niu, Dongdi Wang, Huasheng Zhang, Jianyue Liu, Xujiao Feng, Xiaohui Su, Ju Qiu, Jing Sun, Heping Xu, Catherine Zhang, Kathleen Wang, Yan Bi, Edgar G Engleman, Lei Shen.
      Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
    Keywords:  PD-1; group 2 innate lymphoid cells; insulin resistance; liver kinase B1; mitophagy
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.024
  16. Nat Commun. 2024 May 18. 15(1): 4244
    Mitochondrial respiratory function is preserved under cysteine starvation via glutathione catabolism in NSCLC.
    Nathan P Ward, Sang Jun Yoon, Tyce Flynn, Amanda M Sherwood, Maddison A Olley, Juliana Madej, Gina M DeNicola.
      Cysteine metabolism occurs across cellular compartments to support diverse biological functions and prevent the induction of ferroptosis. Though the disruption of cytosolic cysteine metabolism is implicated in this form of cell death, it is unknown whether the substantial cysteine metabolism resident within the mitochondria is similarly pertinent to ferroptosis. Here, we show that despite the rapid depletion of intracellular cysteine upon loss of extracellular cystine, cysteine-dependent synthesis of Fe-S clusters persists in the mitochondria of lung cancer cells. This promotes a retention of respiratory function and a maintenance of the mitochondrial redox state. Under these limiting conditions, we find that glutathione catabolism by CHAC1 supports the mitochondrial cysteine pool to sustain the function of the Fe-S proteins critical to oxidative metabolism. We find that disrupting Fe-S cluster synthesis under cysteine restriction protects against the induction of ferroptosis, suggesting that the preservation of mitochondrial function is antagonistic to survival under starved conditions. Overall, our findings implicate mitochondrial cysteine metabolism in the induction of ferroptosis and reveal a mechanism of mitochondrial resilience in response to nutrient stress.
    DOI:  https://doi.org/10.1038/s41467-024-48695-2
  17. Sci Transl Med. 2024 May 22. 16(748): eadk1358
    Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice.
    Jeremy M Sullivan, Anna M Bagnell, Jonathan Alevy, Elvia Mena Avila, Ljubica Mihaljević, Pamela C Saavedra-Rivera, Lingling Kong, Jennifer S Huh, Brett A McCray, William H Aisenberg, Aamir R Zuberi, Laurent Bogdanik, Cathleen M Lutz, Zhaozhu Qiu, Katharina A Quinlan, Peter C Searson, Charlotte J Sumner.
      Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether barrier breakdown is sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies to mitigate barrier hyperpermeability are also limited. Dominant missense mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms of hereditary motor neuron disease. To gain insights into the cellular basis of these disorders, we generated knock-in mouse models of TRPV4 channelopathy by introducing two disease-causing mutations (R269C and R232C) into the endogenous mouse Trpv4 gene. TRPV4 mutant mice exhibited weakness, early lethality, and regional motor neuron loss. Genetic deletion of the mutant Trpv4 allele from endothelial cells (but not neurons, glia, or muscle) rescued these phenotypes. Symptomatic mutant mice exhibited focal disruptions of blood-spinal cord barrier (BSCB) integrity, associated with a gain of function of mutant TRPV4 channel activity in neural vascular endothelial cells (NVECs) and alterations of NVEC tight junction structure. Systemic administration of a TRPV4-specific antagonist abrogated channel-mediated BSCB impairments and provided a marked phenotypic rescue of symptomatic mutant mice. Together, our findings show that mutant TRPV4 channels can drive motor neuron degeneration in a non-cell autonomous manner by precipitating focal breakdown of the BSCB. Further, these data highlight the reversibility of TRPV4-mediated BSCB impairments and identify a potential therapeutic strategy for patients with TRPV4 mutations.
    DOI:  https://doi.org/10.1126/scitranslmed.adk1358
  18. Nat Commun. 2024 May 20. 15(1): 4276
    Production of deoxycholic acid by low-abundant microbial species is associated with impaired glucose metabolism.
    Annika Wahlström, Ariel Brumbaugh, Wilhelm Sjöland, Lisa Olsson, Hao Wu, Marcus Henricsson, Annika Lundqvist, Kassem Makki, Stanley L Hazen, Göran Bergström, Hanns-Ulrich Marschall, Michael A Fischbach, Fredrik Bäckhed.
      Alterations in gut microbiota composition are suggested to contribute to cardiometabolic diseases, in part by producing bioactive molecules. Some of the metabolites are produced by very low abundant bacterial taxa, which largely have been neglected due to limits of detection. However, the concentration of microbially produced metabolites from these taxa can still reach high levels and have substantial impact on host physiology. To explore this concept, we focused on the generation of secondary bile acids by 7α-dehydroxylating bacteria and demonstrated that addition of a very low abundant bacteria to a community can change the metabolic output dramatically. We show that Clostridium scindens converts cholic acid into the secondary bile acid deoxycholic acid (DCA) very efficiently even though the abundance of C. scindens is low, but still detectable by digital droplet PCR. We also show that colonization of germ-free female mice with a community containing C. scindens induces DCA production and affects host metabolism. Finally, we show that DCA correlates with impaired glucose metabolism and a worsened lipid profile in individuals with type 2 diabetes, which implies that this metabolic pathway may contribute to the development of cardiometabolic disease.
    DOI:  https://doi.org/10.1038/s41467-024-48543-3
  19. Nat Commun. 2024 May 23. 15(1): 4403
    Single molecule delivery into living cells.
    Chalmers C Chau, Christopher M Maffeo, Aleksei Aksimentiev, Sheena E Radford, Eric W Hewitt, Paolo Actis.
      Controlled manipulation of cultured cells by delivery of exogenous macromolecules is a cornerstone of experimental biology. Here we describe a platform that uses nanopipettes to deliver defined numbers of macromolecules into cultured cell lines and primary cells at single molecule resolution. In the nanoinjection platform, the nanopipette is used as both a scanning ion conductance microscope (SICM) probe and an injection probe. The SICM is used to position the nanopipette above the cell surface before the nanopipette is inserted into the cell into a defined location and to a predefined depth. We demonstrate that the nanoinjection platform enables the quantitative delivery of DNA, globular proteins, and protein fibrils into cells with single molecule resolution and that delivery results in a phenotypic change in the cell that depends on the identity of the molecules introduced. Using experiments and computational modeling, we also show that macromolecular crowding in the cell increases the signal-to-noise ratio for the detection of translocation events, thus the cell itself enhances the detection of the molecules delivered.
    DOI:  https://doi.org/10.1038/s41467-024-48608-3
  20. Cell Stem Cell. 2024 May 14. pii: S1934-5909(24)00176-0. [Epub ahead of print]
    SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
    Shintaro Watanuki, Hiroshi Kobayashi, Yuki Sugiura, Masamichi Yamamoto, Daiki Karigane, Kohei Shiroshita, Yuriko Sorimachi, Takayuki Morikawa, Shinya Fujita, Kotaro Shide, Miho Haraguchi, Shinpei Tamaki, Takumi Mikawa, Hiroshi Kondoh, Hiroyasu Nakano, Kenta Sumiyama, Go Nagamatsu, Nobuhito Goda, Shinichiro Okamoto, Ayako Nakamura-Ishizu, Kazuya Shimoda, Makoto Suematsu, Toshio Suda, Keiyo Takubo.
      Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.
    Keywords:  SDHAF1; adenosine triphosphate; hematopoietic stem cell; mitochondria; stem cell aging; stem cell metabolism; thrombopoietin
    DOI:  https://doi.org/10.1016/j.stem.2024.04.023
  21. Nat Commun. 2024 May 21. 15(1): 4326
    Post-resolution macrophages shape long-term tissue immunity and integrity in a mouse model of pneumococcal pneumonia.
    Karen T Feehan, Hannah E Bridgewater, Jan Stenkiewicz-Witeska, Roel P H De Maeyer, John Ferguson, Matthias Mack, Jeremy Brown, Giuseppe Ercoli, Connar M Mawer, Arne N Akbar, James R W Glanville, Parinaaz Jalali, Olivia V Bracken, Anna Nicolaou, Alexandra C Kendall, Michelle A Sugimoto, Derek W Gilroy.
      Resolving inflammation is thought to return the affected tissue back to homoeostasis but recent evidence supports a non-linear model of resolution involving a phase of prolonged immune activity. Here we show that within days following resolution of Streptococcus pneumoniae-triggered lung inflammation, there is an influx of antigen specific lymphocytes with a memory and tissue-resident phenotype as well as macrophages bearing alveolar or interstitial phenotype. The transcriptome of these macrophages shows enrichment of genes associated with prostaglandin biosynthesis and genes that drive T cell chemotaxis and differentiation. Therapeutic depletion of post-resolution macrophages, inhibition of prostaglandin E2 (PGE2) synthesis or treatment with an EP4 antagonist, MF498, reduce numbers of lung CD4+/CD44+/CD62L+ and CD4+/CD44+/CD62L-/CD27+ T cells as well as their expression of the α-integrin, CD103. The T cells fail to reappear and reactivate upon secondary challenge for up to six weeks following primary infection. Concomitantly, EP4 antagonism through MF498 causes accumulation of lung macrophages and marked tissue fibrosis. Our study thus shows that PGE2 signalling, predominantly via EP4, plays an important role during the second wave of immune activity following resolution of inflammation. This secondary immune activation drives local tissue-resident T cell development while limiting tissue injury.
    DOI:  https://doi.org/10.1038/s41467-024-48138-y
  22. Nat Commun. 2024 May 24. 15(1): 4417
    Validation of human telomere length multi-ancestry meta-analysis association signals identifies POP5 and KBTBD6 as human telomere length regulation genes.
    NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium
      Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of these genes, demonstrating that these loci are related to transcriptional regulation of KBTBD6 and POP5. Our results demonstrate the utility of telomere length GWAS in the identification of telomere length regulation mechanisms and validate KBTBD6 and POP5 as genes affecting telomere length regulation.
    DOI:  https://doi.org/10.1038/s41467-024-48394-y
  23. Science. 2024 May 24. 384(6698): 849-850
    An emerging target for male contraception.
    Jerrett Holdaway, Gunda I Georg.
      An inhibitor of a nonhormonal target is identified using a DNA-encoded chemical library.
    DOI:  https://doi.org/10.1126/science.adp6432
  24. Nat Biomed Eng. 2024 May 22.
    Genome-wide Cas9-mediated screening of essential non-coding regulatory elements via libraries of paired single-guide RNAs.
    Yufeng Li, Minkang Tan, Almira Akkari-Henić, Limin Zhang, Maarten Kip, Shengnan Sun, Jorian J Sepers, Ningning Xu, Yavuz Ariyurek, Susan L Kloet, Richard P Davis, Harald Mikkers, Joshua J Gruber, Michael P Snyder, Xiao Li, Baoxu Pang.
      The functions of non-coding regulatory elements (NCREs), which constitute a major fraction of the human genome, have not been systematically studied. Here we report a method involving libraries of paired single-guide RNAs targeting both ends of an NCRE as a screening system for the Cas9-mediated deletion of thousands of NCREs genome-wide to study their functions in distinct biological contexts. By using K562 and 293T cell lines and human embryonic stem cells, we show that NCREs can have redundant functions, and that many ultra-conserved elements have silencer activity and play essential roles in cell growth and in cellular responses to drugs (notably, the ultra-conserved element PAX6_Tarzan may be critical for heart development, as removing it from human embryonic stem cells led to defects in cardiomyocyte differentiation). The high-throughput screen, which is compatible with single-cell sequencing, may allow for the identification of druggable NCREs.
    DOI:  https://doi.org/10.1038/s41551-024-01204-8
  25. Nature. 2024 May 22.
    Natural proteome diversity links aneuploidy tolerance to protein turnover.
    Julia Muenzner, Pauline Trébulle, Federica Agostini, Henrik Zauber, Christoph B Messner, Martin Steger, Christiane Kilian, Kate Lau, Natalie Barthel, Andrea Lehmann, Kathrin Textoris-Taube, Elodie Caudal, Anna-Sophia Egger, Fatma Amari, Matteo De Chiara, Vadim Demichev, Toni I Gossmann, Michael Mülleder, Gianni Liti, Joseph Schacherer, Matthias Selbach, Judith Berman, Markus Ralser.
      Accessing the natural genetic diversity of species unveils hidden genetic traits, clarifies gene functions and allows the generalizability of laboratory findings to be assessed. One notable discovery made in natural isolates of Saccharomyces cerevisiae is that aneuploidy-an imbalance in chromosome copy numbers-is frequent1,2 (around 20%), which seems to contradict the substantial fitness costs and transient nature of aneuploidy when it is engineered in the laboratory3-5. Here we generate a proteomic resource and merge it with genomic1 and transcriptomic6 data for 796 euploid and aneuploid natural isolates. We find that natural and lab-generated aneuploids differ specifically at the proteome. In lab-generated aneuploids, some proteins-especially subunits of protein complexes-show reduced expression, but the overall protein levels correspond to the aneuploid gene dosage. By contrast, in natural isolates, more than 70% of proteins encoded on aneuploid chromosomes are dosage compensated, and average protein levels are shifted towards the euploid state chromosome-wide. At the molecular level, we detect an induction of structural components of the proteasome, increased levels of ubiquitination, and reveal an interdependency of protein turnover rates and attenuation. Our study thus highlights the role of protein turnover in mediating aneuploidy tolerance, and shows the utility of exploiting the natural diversity of species to attain generalizable molecular insights into complex biological processes.
    DOI:  https://doi.org/10.1038/s41586-024-07442-9
  26. Nat Commun. 2024 May 23. 15(1): 4410
    A nutrient responsive lipase mediates gut-brain communication to regulate insulin secretion in Drosophila.
    Alka Singh, Kandahalli Venkataranganayaka Abhilasha, Kathya R Acharya, Haibo Liu, Niraj K Nirala, Velayoudame Parthibane, Govind Kunduri, Thiruvaimozhi Abimannan, Jacob Tantalla, Lihua Julie Zhu, Jairaj K Acharya, Usha R Acharya.
      Pancreatic β cells secrete insulin in response to glucose elevation to maintain glucose homeostasis. A complex network of inter-organ communication operates to modulate insulin secretion and regulate glucose levels after a meal. Lipids obtained from diet or generated intracellularly are known to amplify glucose-stimulated insulin secretion, however, the underlying mechanisms are not completely understood. Here, we show that a Drosophila secretory lipase, Vaha (CG8093), is synthesized in the midgut and moves to the brain where it concentrates in the insulin-producing cells in a process requiring Lipid Transfer Particle, a lipoprotein originating in the fat body. In response to dietary fat, Vaha stimulates insulin-like peptide release (ILP), and Vaha deficiency results in reduced circulatory ILP and diabetic features including hyperglycemia and hyperlipidemia. Our findings suggest Vaha functions as a diacylglycerol lipase physiologically, by being a molecular link between dietary fat and lipid amplified insulin secretion in a gut-brain axis.
    DOI:  https://doi.org/10.1038/s41467-024-48851-8
  27. J Exp Med. 2024 Aug 05. pii: e20232005. [Epub ahead of print]221(8):
    Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans.
    Undiagnosed Diseases Network
      Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.
    DOI:  https://doi.org/10.1084/jem.20232005
  28. Hum Mol Genet. 2024 May 22. 33(R1): R61-R79
    Illuminating mitochondrial translation through mouse models.
    Laetitia A Hughes, Oliver Rackham, Aleksandra Filipovska.
      Mitochondria are hubs of metabolic activity with a major role in ATP conversion by oxidative phosphorylation (OXPHOS). The mammalian mitochondrial genome encodes 11 mRNAs encoding 13 OXPHOS proteins along with 2 rRNAs and 22 tRNAs, that facilitate their translation on mitoribosomes. Maintaining the internal production of core OXPHOS subunits requires modulation of the mitochondrial capacity to match the cellular requirements and correct insertion of particularly hydrophobic proteins into the inner mitochondrial membrane. The mitochondrial translation system is essential for energy production and defects result in severe, phenotypically diverse diseases, including mitochondrial diseases that typically affect postmitotic tissues with high metabolic demands. Understanding the complex mechanisms that underlie the pathologies of diseases involving impaired mitochondrial translation is key to tailoring specific treatments and effectively targeting the affected organs. Disease mutations have provided a fundamental, yet limited, understanding of mitochondrial protein synthesis, since effective modification of the mitochondrial genome has proven challenging. However, advances in next generation sequencing, cryoelectron microscopy, and multi-omic technologies have revealed unexpected and unusual features of the mitochondrial protein synthesis machinery in the last decade. Genome editing tools have generated unique models that have accelerated our mechanistic understanding of mitochondrial translation and its physiological importance. Here we review the most recent mouse models of disease pathogenesis caused by defects in mitochondrial protein synthesis and discuss their value for preclinical research and therapeutic development.
    Keywords:  animal models; gene expression; mitochondria; protein synthesis
    DOI:  https://doi.org/10.1093/hmg/ddae020
  29. Science. 2024 May 24. 384(6698): eadi5199
    Single-cell genomics and regulatory networks for 388 human brains.
    PsychENCODE Consortium‡
      Single-cell genomics is a powerful tool for studying heterogeneous tissues such as the brain. Yet little is understood about how genetic variants influence cell-level gene expression. Addressing this, we uniformly processed single-nuclei, multiomics datasets into a resource comprising >2.8 million nuclei from the prefrontal cortex across 388 individuals. For 28 cell types, we assessed population-level variation in expression and chromatin across gene families and drug targets. We identified >550,000 cell type-specific regulatory elements and >1.4 million single-cell expression quantitative trait loci, which we used to build cell-type regulatory and cell-to-cell communication networks. These networks manifest cellular changes in aging and neuropsychiatric disorders. We further constructed an integrative model accurately imputing single-cell expression and simulating perturbations; the model prioritized ~250 disease-risk genes and drug targets with associated cell types.
    DOI:  https://doi.org/10.1126/science.adi5199
  30. Cell Rep Med. 2024 May 21. pii: S2666-3791(24)00248-9. [Epub ahead of print]5(5): 101556
    Transcriptomic and spatial dissection of human ex vivo right atrial tissue reveals proinflammatory microvascular changes in ischemic heart disease.
    Suvi Linna-Kuosmanen, Eloi Schmauch, Kyriakitsa Galani, Johannes Ojanen, Carles A Boix, Tiit Örd, Anu Toropainen, Prosanta K Singha, Pierre R Moreau, Kristiina Harju, Adriana Blazeski, Åsa Segerstolpe, Veikko Lahtinen, Lei Hou, Kai Kang, Elamaran Meibalan, Leandro Z Agudelo, Hannu Kokki, Jari Halonen, Juho Jalkanen, Jarmo Gunn, Calum A MacRae, Maija Hollmén, Juha E K Hartikainen, Minna U Kaikkonen, Guillermo García-Cardeña, Pasi Tavi, Tuomas Kiviniemi, Manolis Kellis.
      Cardiovascular disease plays a central role in the electrical and structural remodeling of the right atrium, predisposing to arrhythmias, heart failure, and sudden death. Here, we dissect with single-nuclei RNA sequencing (snRNA-seq) and spatial transcriptomics the gene expression changes in the human ex vivo right atrial tissue and pericardial fluid in ischemic heart disease, myocardial infarction, and ischemic and non-ischemic heart failure using asymptomatic patients with valvular disease who undergo preventive surgery as the control group. We reveal substantial differences in disease-associated gene expression in all cell types, collectively suggesting inflammatory microvascular dysfunction and changes in the right atrial tissue composition as the valvular and vascular diseases progress into heart failure. The data collectively suggest that investigation of human cardiovascular disease should expand to all functionally important parts of the heart, which may help us to identify mechanisms promoting more severe types of the disease.
    Keywords:  cardiovascular disease; disease mechanism; genetic variation; heart; heart failure; inflammation; ischemic heart disease; single cell; spatial transcriptomics; transcriptomics
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101556
  31. Science. 2024 May 24. 384(6698): eadh7688
    Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms.
    Ashok Patowary, Pan Zhang, Connor Jops, Celine K Vuong, Xinzhou Ge, Kangcheng Hou, Minsoo Kim, Naihua Gong, Michael Margolis, Daniel Vo, Xusheng Wang, Chunyu Liu, Bogdan Pasaniuc, Jingyi Jessica Li, Michael J Gandal, Luis de la Torre-Ubieta.
      RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type-specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity-regulated by RNA binding proteins-in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders.
    DOI:  https://doi.org/10.1126/science.adh7688
  32. Nat Commun. 2024 May 20. 15(1): 4260
    Integrating single cell expression quantitative trait loci summary statistics to understand complex trait risk genes.
    Lida Wang, Chachrit Khunsriraksakul, Havell Markus, Dieyi Chen, Fan Zhang, Fang Chen, Xiaowei Zhan, Laura Carrel, Dajiang J Liu, Bibo Jiang.
      Transcriptome-wide association study (TWAS) is a popular approach to dissect the functional consequence of disease associated non-coding variants. Most existing TWAS use bulk tissues and may not have the resolution to reveal cell-type specific target genes. Single-cell expression quantitative trait loci (sc-eQTL) datasets are emerging. The largest bulk- and sc-eQTL datasets are most conveniently available as summary statistics, but have not been broadly utilized in TWAS. Here, we present a new method EXPRESSO (EXpression PREdiction with Summary Statistics Only), to analyze sc-eQTL summary statistics, which also integrates 3D genomic data and epigenomic annotation to prioritize causal variants. EXPRESSO substantially improves existing methods. We apply EXPRESSO to analyze multi-ancestry GWAS datasets for 14 autoimmune diseases. EXPRESSO uniquely identifies 958 novel gene x trait associations, which is 26% more than the second-best method. Among them, 492 are unique to cell type level analysis and missed by TWAS using whole blood. We also develop a cell type aware drug repurposing pipeline, which leverages EXPRESSO results to identify drug compounds that can reverse disease gene expressions in relevant cell types. Our results point to multiple drugs with therapeutic potentials, including metformin for type 1 diabetes, and vitamin K for ulcerative colitis.
    DOI:  https://doi.org/10.1038/s41467-024-48143-1
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