bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒07‒17
34 papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. A reference single-cell regulomic and transcriptomic map of cynomolgus monkeys.
  2. CD8 lymphocytes mitigate HIV-1 persistence in lymph node follicular helper T cells during hyperacute-treated infection.
  3. The shape of things to come: structural insights into how prion proteins encipher heritable information.
  4. Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA.
  5. Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity.
  6. ZBTB46 defines and regulates ILC3s that protect the intestine.
  7. Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration.
  8. Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies.
  9. YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and tumorigenesis.
  10. The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance.
  11. Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity.
  12. Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex.
  13. Trigger factor both holds and folds its client proteins.
  14. Selective expression of variant surface antigens enables Plasmodium falciparum to evade immune clearance in vivo.
  15. Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy.
  16. Systematic discovery and perturbation of regulatory genes in human T cells reveals the architecture of immune networks.
  17. Mesp1 controls the chromatin and enhancer landscapes essential for spatiotemporal patterning of early cardiovascular progenitors.
  18. Structure of the nutrient-sensing hub GATOR2.
  19. Decoupling PER phosphorylation, stability and rhythmic expression from circadian clock function by abolishing PER-CK1 interaction.
  20. Characterizing cis-regulatory elements using single-cell epigenomics.
  21. New epigenetic regulators of T cell exhaustion.
  22. Fra-2 Is a Dominant Negative Regulator of Natural Killer Cell Development.
  23. Mucosal viral infection induces a regulatory T cell activation phenotype distinct from tissue residency in mouse and human tissues.
  24. Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing.
  25. A sequence-based global map of regulatory activity for deciphering human genetics.
  26. Transcriptional enhancers at 40: evolution of a viral DNA element to nuclear architectural structures.
  27. Microglia coordinate cellular interactions during spinal cord repair in mice.
  28. Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells.
  29. Neuromedin U promotes human type 2 immune responses.
  30. Within-host evolution of a gut pathobiont facilitates liver translocation.
  31. Brain organoids: the quest to decipher human-specific features of brain development.
  32. Programmable CRISPR-Cas9 microneedle patch for long-term capture and real-time monitoring of universal cell-free DNA.
  33. How do thin people stay that way? More activity is not always the answer.
  34. Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism.
  1. Nat Commun. 2022 Jul 13. 13(1): 4069
    A reference single-cell regulomic and transcriptomic map of cynomolgus monkeys.
    Jiao Qu, Fa Yang, Tao Zhu, Yingshuo Wang, Wen Fang, Yan Ding, Xue Zhao, Xianjia Qi, Qiangmin Xie, Ming Chen, Qiang Xu, Yicheng Xie, Yang Sun, Dijun Chen.
      Non-human primates are attractive laboratory animal models that accurately reflect both developmental and pathological features of humans. Here we present a compendium of cell types across multiple organs in cynomolgus monkeys (Macaca fascicularis) using both single-cell chromatin accessibility and RNA sequencing data. The integrated cell map enables in-depth dissection and comparison of molecular dynamics, cell-type compositions and cellular heterogeneity across multiple tissues and organs. Using single-cell transcriptomic data, we infer pseudotime cell trajectories and cell-cell communications to uncover key molecular signatures underlying their cellular processes. Furthermore, we identify various cell-specific cis-regulatory elements and construct organ-specific gene regulatory networks at the single-cell level. Finally, we perform comparative analyses of single-cell landscapes among mouse, monkey and human. We show that cynomolgus monkey has strikingly higher degree of similarities in terms of immune-associated gene expression patterns and cellular communications to human than mouse. Taken together, our study provides a valuable resource for non-human primate cell biology.
    DOI:  https://doi.org/10.1038/s41467-022-31770-x
  2. Nat Commun. 2022 Jul 12. 13(1): 4041
    CD8 lymphocytes mitigate HIV-1 persistence in lymph node follicular helper T cells during hyperacute-treated infection.
    Omolara O Baiyegunhi, Jaclyn Mann, Trevor Khaba, Thandeka Nkosi, Anele Mbatha, Funsho Ogunshola, Caroline Chasara, Nasreen Ismail, Thandekile Ngubane, Ismail Jajbhay, Johan Pansegrouw, Krista L Dong, Bruce D Walker, Thumbi Ndung'u, Zaza M Ndhlovu.
      HIV persistence in tissue sites despite ART is a major barrier to HIV cure. Detailed studies of HIV-infected cells and immune responses in native lymph node tissue environment is critical for gaining insight into immune mechanisms impacting HIV persistence and clearance in tissue sanctuary sites. We compared HIV persistence and HIV-specific T cell responses in lymph node biopsies obtained from 14 individuals who initiated therapy in Fiebig stages I/II, 5 persons treated in Fiebig stages III-V and 17 late treated individuals who initiated ART in Fiebig VI and beyond. Using multicolor immunofluorescence staining and in situ hybridization, we detect HIV RNA and/or protein in 12 of 14 Fiebig I/II treated persons on suppressive therapy for 1 to 55 months, and in late treated persons with persistent antigens. CXCR3+ T follicular helper cells harbor the greatest amounts of gag mRNA transcripts. Notably, HIV-specific CD8+ T cells responses are associated with lower HIV antigen burden, suggesting that these responses may contribute to HIV suppression in lymph nodes during therapy. These results reveal HIV persistence despite the initiation of ART in hyperacute infection and highlight the contribution of virus-specific responses to HIV suppression in tissue sanctuaries during suppressive ART.
    DOI:  https://doi.org/10.1038/s41467-022-31692-8
  3. Nat Commun. 2022 Jul 13. 13(1): 4003
    The shape of things to come: structural insights into how prion proteins encipher heritable information.
    Glenn C Telling.
      
    DOI:  https://doi.org/10.1038/s41467-022-31460-8
  4. Nat Commun. 2022 Jul 09. 13(1): 3988
    Chromatin sequesters pioneer transcription factor Sox2 from exerting force on DNA.
    Tuan Nguyen, Sai Li, Jeremy T-H Chang, John W Watters, Htet Ng, Adewola Osunsade, Yael David, Shixin Liu.
      Biomolecular condensation constitutes an emerging mechanism for transcriptional regulation. Recent studies suggest that the co-condensation between transcription factors (TFs) and DNA can generate mechanical forces driving genome rearrangements. However, the reported forces generated by protein-DNA co-condensation are typically below one piconewton (pN), questioning its physiological significance. Moreover, the force-generating capacity of these condensates in the chromatin context remains unknown. Here, we show that Sox2, a nucleosome-binding pioneer TF, forms co-condensates with DNA and generates forces up to 7 pN, exerting considerable mechanical tension on DNA strands. We find that the disordered domains of Sox2 are required for maximum force generation but not for condensate formation. Furthermore, we show that nucleosomes dramatically attenuate the mechanical stress exerted by Sox2 by sequestering it from coalescing on bare DNA. Our findings reveal that TF-mediated DNA condensation can exert significant mechanical stress on the genome which can nonetheless be attenuated by the chromatin architecture.
    DOI:  https://doi.org/10.1038/s41467-022-31738-x
  5. Nat Commun. 2022 Jul 14. 13(1): 4075
    Cell-autonomous Hedgehog signaling controls Th17 polarization and pathogenicity.
    Joachim Hanna, Flavio Beke, Louise M O'Brien, Chrysa Kapeni, Hung-Chang Chen, Valentina Carbonaro, Alexander B Kim, Kamal Kishore, Timon E Adolph, Mikkel-Ole Skjoedt, Karsten Skjoedt, Marc de la Roche, Maike de la Roche.
      Th17 cells are key drivers of autoimmune disease. However, the signaling pathways regulating Th17 polarization are poorly understood. Hedgehog signaling regulates cell fate decisions during embryogenesis and adult tissue patterning. Here we find that cell-autonomous Hedgehog signaling, independent of exogenous ligands, selectively drives the polarization of Th17 cells but not other T helper cell subsets. We show that endogenous Hedgehog ligand, Ihh, signals to activate both canonical and non-canonical Hedgehog pathways through Gli3 and AMPK. We demonstrate that Hedgehog pathway inhibition with either the clinically-approved small molecule inhibitor vismodegib or genetic ablation of Ihh in CD4+ T cells greatly diminishes disease severity in two mouse models of intestinal inflammation. We confirm that Hedgehog pathway expression is upregulated in tissue from human ulcerative colitis patients and correlates with Th17 marker expression. This work implicates Hedgehog signaling in Th17 polarization and intestinal immunopathology and indicates the potential therapeutic use of Hedgehog inhibitors in the treatment of inflammatory bowel disease.
    DOI:  https://doi.org/10.1038/s41467-022-31722-5
  6. Nature. 2022 Jul 13.
    ZBTB46 defines and regulates ILC3s that protect the intestine.
    JRI Live Cell Bank
      RORγt is a lineage-specifying transcription factor that is expressed by immune cells that are enriched in the gastrointestinal tract and promote immunity, inflammation and tissue homeostasis1-15. However, fundamental questions remain with regard to the cellular heterogeneity among these cell types, the mechanisms that control protective versus inflammatory properties and their functional redundancy. Here we define all RORγt+ immune cells in the intestine at single-cell resolution and identify a subset of group 3 innate lymphoid cells (ILC3s) that expresses ZBTB46, a transcription factor specifying conventional dendritic cells16-20. ZBTB46 is robustly expressed by CCR6+ lymphoid-tissue-inducer-like ILC3s that are developmentally and phenotypically distinct from conventional dendritic cells, and its expression is imprinted by RORγt, fine-tuned by microbiota-derived signals and increased by pro-inflammatory cytokines. ZBTB46 restrains the inflammatory properties of ILC3s, including the OX40L-dependent expansion of T helper 17 cells and the exacerbated intestinal inflammation that occurs after enteric infection. Finally, ZBTB46+ ILC3s are a major source of IL-22, and selective depletion of this population renders mice susceptible to enteric infection and associated intestinal inflammation. These results show that ZBTB46 is a transcription factor that is shared between conventional dendritic cells and ILC3s, and identify a cell-intrinsic function for ZBTB46 in restraining the pro-inflammatory properties of ILC3s and a non-redundant role for ZBTB46+ ILC3s in orchestrating intestinal health.
    DOI:  https://doi.org/10.1038/s41586-022-04934-4
  7. Nat Commun. 2022 Jul 11. 13(1): 4018
    Single-cell analysis highlights differences in druggable pathways underlying adaptive or fibrotic kidney regeneration.
    Michael S Balzer, Tomohito Doke, Ya-Wen Yang, Daniel L Aldridge, Hailong Hu, Hung Mai, Dhanunjay Mukhi, Ziyuan Ma, Rojesh Shrestha, Matthew B Palmer, Christopher A Hunter, Katalin Susztak.
      The kidney has tremendous capacity to repair after acute injury, however, pathways guiding adaptive and fibrotic repair are poorly understood. We developed a model of adaptive and fibrotic kidney regeneration by titrating ischemic injury dose. We performed detailed biochemical and histological analysis and profiled transcriptomic changes at bulk and single-cell level (> 110,000 cells) over time. Our analysis highlights kidney proximal tubule cells as key susceptible cells to injury. Adaptive proximal tubule repair correlated with fatty acid oxidation and oxidative phosphorylation. We identify a specific maladaptive/profibrotic proximal tubule cluster after long ischemia, which expresses proinflammatory and profibrotic cytokines and myeloid cell chemotactic factors. Druggability analysis highlights pyroptosis/ferroptosis as vulnerable pathways in these profibrotic cells. Pharmacological targeting of pyroptosis/ferroptosis in vivo pushed cells towards adaptive repair and ameliorates fibrosis. In summary, our single-cell analysis defines key differences in adaptive and fibrotic repair and identifies druggable pathways for pharmacological intervention to prevent kidney fibrosis.
    DOI:  https://doi.org/10.1038/s41467-022-31772-9
  8. Nat Commun. 2022 Jul 14. 13(1): 4095
    Structures of β1-adrenergic receptor in complex with Gs and ligands of different efficacies.
    Minfei Su, Navid Paknejad, Lan Zhu, Jinan Wang, Hung Nguyen Do, Yinglong Miao, Wei Liu, Richard K Hite, Xin-Yun Huang.
      G-protein-coupled receptors (GPCRs) receive signals from ligands with different efficacies, and transduce to heterotrimeric G-proteins to generate different degrees of physiological responses. Previous studies revealed how ligands with different efficacies activate GPCRs. Here, we investigate how a GPCR activates G-proteins upon binding ligands with different efficacies. We report the cryo-EM structures of β1-adrenergic receptor (β1-AR) in complex with Gs (GαsGβ1Gγ2) and a partial agonist or a very weak partial agonist, and compare them to the β1-AR-Gs structure in complex with a full agonist. Analyses reveal similar overall complex architecture, with local conformational differences. Cellular functional studies with mutations of β1-AR residues show effects on the cellular signaling from β1-AR to the cAMP response initiated by the three different ligands, with residue-specific functional differences. Biochemical investigations uncover that the intermediate state complex comprising β1-AR and nucleotide-free Gs is more stable when binding a full agonist than a partial agonist. Molecular dynamics simulations support the local conformational flexibilities and different stabilities among the three complexes. These data provide insights into the ligand efficacy in the activation of GPCRs and G-proteins.
    DOI:  https://doi.org/10.1038/s41467-022-31823-1
  9. Nat Genet. 2022 Jul 14.
    YAP induces an oncogenic transcriptional program through TET1-mediated epigenetic remodeling in liver growth and tumorigenesis.
    Bo-Kuan Wu, Szu-Chieh Mei, Elizabeth H Chen, Yonggang Zheng, Duojia Pan.
      Epigenetic remodeling is essential for oncogene-induced cellular transformation and malignancy. In contrast to histone post-translational modifications, how DNA methylation is remodeled by oncogenic signaling remains poorly understood. The oncoprotein YAP, a coactivator of the TEAD transcription factors mediating Hippo signaling, is widely activated in human cancers. Here, we identify the 5-methylcytosine dioxygenase TET1 as a direct YAP target and a master regulator that coordinates the genome-wide epigenetic and transcriptional reprogramming of YAP target genes in the liver. YAP activation induces the expression of TET1, which physically interacts with TEAD to cause regional DNA demethylation, histone H3K27 acetylation and chromatin opening in YAP target genes to facilitate transcriptional activation. Loss of TET1 not only reverses YAP-induced epigenetic and transcriptional changes but also suppresses YAP-induced hepatomegaly and tumorigenesis. These findings exemplify how oncogenic signaling regulates the site specificity of DNA demethylation to promote tumorigenesis and implicate TET1 as a potential target for modulating YAP signaling in physiology and disease.
    DOI:  https://doi.org/10.1038/s41588-022-01119-7
  10. Nat Commun. 2022 Jul 15. 13(1): 4121
    The surfaceome of multiple myeloma cells suggests potential immunotherapeutic strategies and protein markers of drug resistance.
    Ian D Ferguson, Bonell Patiño-Escobar, Sami T Tuomivaara, Yu-Hsiu T Lin, Matthew A Nix, Kevin K Leung, Corynn Kasap, Emilio Ramos, Wilson Nieves Vasquez, Alexis Talbot, Martina Hale, Akul Naik, Audrey Kishishita, Priya Choudhry, Antonia Lopez-Girona, Weili Miao, Sandy W Wong, Jeffrey L Wolf, Thomas G Martin, Nina Shah, Scott Vandenberg, Sonam Prakash, Lenka Besse, Christoph Driessen, Avery D Posey, R Dyche Mullins, Justin Eyquem, James A Wells, Arun P Wiita.
      The myeloma surface proteome (surfaceome) determines tumor interaction with the microenvironment and serves as an emerging arena for therapeutic development. Here, we use glycoprotein capture proteomics to define the myeloma surfaceome at baseline, in drug resistance, and in response to acute drug treatment. We provide a scoring system for surface antigens and identify CCR10 as a promising target in this disease expressed widely on malignant plasma cells. We engineer proof-of-principle chimeric antigen receptor (CAR) T-cells targeting CCR10 using its natural ligand CCL27. In myeloma models we identify proteins that could serve as markers of resistance to bortezomib and lenalidomide, including CD53, CD10, EVI2B, and CD33. We find that acute lenalidomide treatment increases activity of MUC1-targeting CAR-T cells through antigen upregulation. Finally, we develop a miniaturized surface proteomic protocol for profiling primary plasma cell samples with low inputs. These approaches and datasets may contribute to the biological, therapeutic, and diagnostic understanding of myeloma.
    DOI:  https://doi.org/10.1038/s41467-022-31810-6
  11. Nat Commun. 2022 Jul 14. 13(1): 4073
    Natural Killer cells demonstrate distinct eQTL and transcriptome-wide disease associations, highlighting their role in autoimmunity.
    James J Gilchrist, Seiko Makino, Vivek Naranbhai, Piyush K Sharma, Surya Koturan, Orion Tong, Chelsea A Taylor, Robert A Watson, Alba Verge de Los Aires, Rosalin Cooper, Evelyn Lau, Sara Danielli, Dan Hameiri-Bowen, Wanseon Lee, Esther Ng, Justin Whalley, Julian C Knight, Benjamin P Fairfax.
      Natural Killer cells are innate lymphocytes with central roles in immunosurveillance and are implicated in autoimmune pathogenesis. The degree to which regulatory variants affect Natural Killer cell gene expression is poorly understood. Here we perform expression quantitative trait locus mapping of negatively selected Natural Killer cells from a population of healthy Europeans (n = 245). We find a significant subset of genes demonstrate expression quantitative trait loci specific to Natural Killer cells and these are highly informative of human disease, in particular autoimmunity. A Natural Killer cell transcriptome-wide association study across five common autoimmune diseases identifies further novel associations at 27 genes. In addition to these cis observations, we find novel master-regulatory regions impacting expression of trans gene networks at regions including 19q13.4, the Killer cell Immunoglobulin-like Receptor region, GNLY, MC1R and UVSSA. Our findings provide new insights into the unique biology of Natural Killer cells, demonstrating markedly different expression quantitative trait loci from other immune cells, with implications for disease mechanisms.
    DOI:  https://doi.org/10.1038/s41467-022-31626-4
  12. Nature. 2022 Jul 13.
    Structure-function analysis of the SHOC2-MRAS-PP1C holophosphatase complex.
    Jason J Kwon, Behnoush Hajian, Yuemin Bian, Lucy C Young, Alvaro J Amor, James R Fuller, Cara V Fraley, Abbey M Sykes, Jonathan So, Joshua Pan, Laura Baker, Sun Joo Lee, Douglas B Wheeler, David L Mayhew, Nicole S Persky, Xiaoping Yang, David E Root, Anthony M Barsotti, Andrew W Stamford, Charles K Perry, Alex Burgin, Frank McCormick, Christopher T Lemke, William C Hahn, Andrew J Aguirre.
      Receptor tyrosine kinase (RTK)-RAS signalling through the downstream mitogen-activated protein kinase (MAPK) cascade regulates cell proliferation and survival. The SHOC2-MRAS-PP1C holophosphatase complex functions as a key regulator of RTK-RAS signalling by removing an inhibitory phosphorylation event on the RAF family of proteins to potentiate MAPK signalling1. SHOC2 forms a ternary complex with MRAS and PP1C, and human germline gain-of-function mutations in this complex result in congenital RASopathy syndromes2-5. However, the structure and assembly of this complex are poorly understood. Here we use cryo-electron microscopy to resolve the structure of the SHOC2-MRAS-PP1C complex. We define the biophysical principles of holoenzyme interactions, elucidate the assembly order of the complex, and systematically interrogate the functional consequence of nearly all of the possible missense variants of SHOC2 through deep mutational scanning. We show that SHOC2 binds PP1C and MRAS through the concave surface of the leucine-rich repeat region and further engages PP1C through the N-terminal disordered region that contains a cryptic RVXF motif. Complex formation is initially mediated by interactions between SHOC2 and PP1C and is stabilized by the binding of GTP-loaded MRAS. These observations explain how mutant versions of SHOC2 in RASopathies and cancer stabilize the interactions of complex members to enhance holophosphatase activity. Together, this integrative structure-function model comprehensively defines key binding interactions within the SHOC2-MRAS-PP1C holophosphatase complex and will inform therapeutic development .
    DOI:  https://doi.org/10.1038/s41586-022-04928-2
  13. Nat Commun. 2022 Jul 15. 13(1): 4126
    Trigger factor both holds and folds its client proteins.
    Kevin Wu, Thomas C Minshull, Sheena E Radford, Antonio N Calabrese, James C A Bardwell.
      ATP-independent chaperones like trigger factor are generally assumed to play passive roles in protein folding by acting as holding chaperones. Here we show that trigger factor plays a more active role. Consistent with a role as an aggregation inhibiting chaperone, we find that trigger factor rapidly binds to partially folded glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and prevents it from non-productive self-association by shielding oligomeric interfaces. In the traditional view of holding chaperone action, trigger factor would then be expected to transfer its client to a chaperone foldase system for complete folding. Unexpectedly, we noticed that GAPDH folds into a monomeric but otherwise rather native-like intermediate state while trigger factor-bound. Upon release from trigger factor, the mostly folded monomeric GAPDH rapidly self-associates into its native tetramer and acquires enzymatic activity without needing additional folding factors. The mechanism we propose here for trigger factor bridges the holding and folding activities of chaperone function.
    DOI:  https://doi.org/10.1038/s41467-022-31767-6
  14. Nat Commun. 2022 Jul 13. 13(1): 4067
    Selective expression of variant surface antigens enables Plasmodium falciparum to evade immune clearance in vivo.
    Marvin Chew, Weijian Ye, Radoslaw Igor Omelianczyk, Charisse Flerida Pasaje, Regina Hoo, Qingfeng Chen, Jacquin C Niles, Jianzhu Chen, Peter Preiser.
      Plasmodium falciparum has developed extensive mechanisms to evade host immune clearance. Currently, most of our understanding is based on in vitro studies of individual parasite variant surface antigens and how this relates to the processes in vivo is not well-understood. Here, we have used a humanized mouse model to identify parasite factors important for in vivo growth. We show that upregulation of the specific PfEMP1, VAR2CSA, provides the parasite with protection from macrophage phagocytosis and clearance in the humanized mice. Furthermore, parasites adapted to thrive in the humanized mice show reduced NK cell-mediated killing through interaction with the immune inhibitory receptor, LILRB1. Taken together, these findings reveal new insights into the molecular and cellular mechanisms that the parasite utilizes to coordinate immune escape in vivo. Identification and targeting of these specific parasite variant surface antigens crucial for immune evasion provides a unique approach for therapy.
    DOI:  https://doi.org/10.1038/s41467-022-31741-2
  15. Nat Commun. 2022 Jul 15. 13(1): 4118
    Hypoxia induces HIF1α-dependent epigenetic vulnerability in triple negative breast cancer to confer immune effector dysfunction and resistance to anti-PD-1 immunotherapy.
    Shijun Ma, Yue Zhao, Wee Chyan Lee, Li-Teng Ong, Puay Leng Lee, Zemin Jiang, Gokce Oguz, Zhitong Niu, Min Liu, Jian Yuan Goh, Wenyu Wang, Matias A Bustos, Sidse Ehmsen, Adaikalavan Ramasamy, Dave S B Hoon, Henrik J Ditzel, Ern Yu Tan, Qingfeng Chen, Qiang Yu.
      The hypoxic tumor microenvironment has been implicated in immune escape, but the underlying mechanism remains elusive. Using an in vitro culture system modeling human T cell dysfunction and exhaustion in triple-negative breast cancer (TNBC), we find that hypoxia suppresses immune effector gene expression, including in T and NK cells, resulting in immune effector cell dysfunction and resistance to immunotherapy. We demonstrate that hypoxia-induced factor 1α (HIF1α) interaction with HDAC1 and concurrent PRC2 dependency causes chromatin remolding resulting in epigenetic suppression of effector genes and subsequent immune dysfunction. Targeting HIF1α and the associated epigenetic machinery can reverse the immune effector dysfunction and overcome resistance to PD-1 blockade, as demonstrated both in vitro and in vivo using syngeneic and humanized mice models. These findings identify a HIF1α-mediated epigenetic mechanism in immune dysfunction and provide a potential strategy to overcome immune resistance in TNBC.
    DOI:  https://doi.org/10.1038/s41467-022-31764-9
  16. Nat Genet. 2022 Jul 11.
    Systematic discovery and perturbation of regulatory genes in human T cells reveals the architecture of immune networks.
    Jacob W Freimer, Oren Shaked, Sahin Naqvi, Nasa Sinnott-Armstrong, Arwa Kathiria, Christian M Garrido, Amy F Chen, Jessica T Cortez, William J Greenleaf, Jonathan K Pritchard, Alexander Marson.
      Gene regulatory networks ensure that important genes are expressed at precise levels. When gene expression is sufficiently perturbed, it can lead to disease. To understand how gene expression disruptions percolate through a network, we must first map connections between regulatory genes and their downstream targets. However, we lack comprehensive knowledge of the upstream regulators of most genes. Here, we developed an approach for systematic discovery of upstream regulators of critical immune factors-IL2RA, IL-2 and CTLA4-in primary human T cells. Then, we mapped the network of the target genes of these regulators and putative cis-regulatory elements using CRISPR perturbations, RNA-seq and ATAC-seq. These regulators form densely interconnected networks with extensive feedback loops. Furthermore, this network is enriched for immune-associated disease variants and genes. These results provide insight into how immune-associated disease genes are regulated in T cells and broader principles about the structure of human gene regulatory networks.
    DOI:  https://doi.org/10.1038/s41588-022-01106-y
  17. Nat Cell Biol. 2022 Jul;24(7): 1114-1128
    Mesp1 controls the chromatin and enhancer landscapes essential for spatiotemporal patterning of early cardiovascular progenitors.
    Xionghui Lin, Benjamin Swedlund, Mai-Linh N Ton, Shila Ghazanfar, Carolina Guibentif, Catherine Paulissen, Elodie Baudelet, Elise Plaindoux, Younes Achouri, Emilie Calonne, Christine Dubois, William Mansfield, Stéphane Zaffran, John C Marioni, Francois Fuks, Berthold Göttgens, Fabienne Lescroart, Cédric Blanpain.
      The mammalian heart arises from various populations of Mesp1-expressing cardiovascular progenitors (CPs) that are specified during the early stages of gastrulation. Mesp1 is a transcription factor that acts as a master regulator of CP specification and differentiation. However, how Mesp1 regulates the chromatin landscape of nascent mesodermal cells to define the temporal and spatial patterning of the distinct populations of CPs remains unknown. Here, by combining ChIP-seq, RNA-seq and ATAC-seq during mouse pluripotent stem cell differentiation, we defined the dynamic remodelling of the chromatin landscape mediated by Mesp1. We identified different enhancers that are temporally regulated to erase the pluripotent state and specify the pools of CPs that mediate heart development. We identified Zic2 and Zic3 as essential cofactors that act with Mesp1 to regulate its transcription-factor activity at key mesodermal enhancers, thereby regulating the chromatin remodelling and gene expression associated with the specification of the different populations of CPs in vivo. Our study identifies the dynamics of the chromatin landscape and enhancer remodelling associated with temporal patterning of early mesodermal cells into the distinct populations of CPs that mediate heart development.
    DOI:  https://doi.org/10.1038/s41556-022-00947-3
  18. Nature. 2022 Jul 13.
    Structure of the nutrient-sensing hub GATOR2.
    Max L Valenstein, Kacper B Rogala, Pranav V Lalgudi, Edward J Brignole, Xin Gu, Robert A Saxton, Lynne Chantranupong, Jonas Kolibius, Jan-Philipp Quast, David M Sabatini.
      Mechanistic target of rapamycin complex 1 (mTORC1) controls growth by regulating anabolic and catabolic processes in response to environmental cues, including nutrients1,2. Amino acids signal to mTORC1 through the Rag GTPases, which are regulated by several protein complexes, including GATOR1 and GATOR2. GATOR2, which has five components (WDR24, MIOS, WDR59, SEH1L and SEC13), is required for amino acids to activate mTORC1 and interacts with the leucine and arginine sensors SESN2 and CASTOR1, respectively3-5. Despite this central role in nutrient sensing, GATOR2 remains mysterious as its subunit stoichiometry, biochemical function and structure are unknown. Here we used cryo-electron microscopy to determine the three-dimensional structure of the human GATOR2 complex. We found that GATOR2 adopts a large (1.1 MDa), two-fold symmetric, cage-like architecture, supported by an octagonal scaffold and decorated with eight pairs of WD40 β-propellers. The scaffold contains two WDR24, four MIOS and two WDR59 subunits circularized via two distinct types of junction involving non-catalytic RING domains and α-solenoids. Integration of SEH1L and SEC13 into the scaffold through β-propeller blade donation stabilizes the GATOR2 complex and reveals an evolutionary relationship to the nuclear pore and membrane-coating complexes6. The scaffold orients the WD40 β-propeller dimers, which mediate interactions with SESN2, CASTOR1 and GATOR1. Our work reveals the structure of an essential component of the nutrient-sensing machinery and provides a foundation for understanding the function of GATOR2 within the mTORC1 pathway.
    DOI:  https://doi.org/10.1038/s41586-022-04939-z
  19. Nat Commun. 2022 Jul 09. 13(1): 3991
    Decoupling PER phosphorylation, stability and rhythmic expression from circadian clock function by abolishing PER-CK1 interaction.
    Yang An, Baoshi Yuan, Pancheng Xie, Yue Gu, Zhiwei Liu, Tao Wang, Zhihao Li, Ying Xu, Yi Liu.
      Robust rhythms of abundances and phosphorylation profiles of PERIOD proteins were thought be the master rhythms that drive mammalian circadian clock functions. PER stability was proposed to be a major determinant of period length. In mammals, CK1 forms stable complexes with PER. Here we identify the PER residues essential for PER-CK1 interaction. In cells and in mice, their mutation abolishes PER phosphorylation and CLOCK hyperphosphorylation, resulting in PER stabilization, arrhythmic PER abundance and impaired negative feedback process, indicating that PER acts as the CK1 scaffold in circadian feedback mechanism. Surprisingly, the mutant mice exhibit robust short period locomotor activity and other physiological rhythms but low amplitude molecular rhythms. PER-CK1 interaction has two opposing roles in regulating CLOCK-BMAL1 activity. These results indicate that the circadian clock can function independently of PER phosphorylation and abundance rhythms due to another PER-CRY-dependent feedback mechanism and that period length can be uncoupled from PER stability.
    DOI:  https://doi.org/10.1038/s41467-022-31715-4
  20. Nat Rev Genet. 2022 Jul 15.
    Characterizing cis-regulatory elements using single-cell epigenomics.
    Sebastian Preissl, Kyle J Gaulton, Bing Ren.
      Cell type-specific gene expression patterns and dynamics during development or in disease are controlled by cis-regulatory elements (CREs), such as promoters and enhancers. Distinct classes of CREs can be characterized by their epigenomic features, including DNA methylation, chromatin accessibility, combinations of histone modifications and conformation of local chromatin. Tremendous progress has been made in cataloguing CREs in the human genome using bulk transcriptomic and epigenomic methods. However, single-cell epigenomic and multi-omic technologies have the potential to provide deeper insight into cell type-specific gene regulatory programmes as well as into how they change during development, in response to environmental cues and through disease pathogenesis. Here, we highlight recent advances in single-cell epigenomic methods and analytical tools and discuss their readiness for human tissue profiling.
    DOI:  https://doi.org/10.1038/s41576-022-00509-1
  21. Cancer Cell. 2022 Jul 11. pii: S1535-6108(22)00272-0. [Epub ahead of print]40(7): 708-710
    New epigenetic regulators of T cell exhaustion.
    Haydn Kissick, Rafi Ahmed.
      In this issue of Cancer Cell, Belk et al. perform an in vitro CRISPR screen to identify genes that regulate CD8+ T cell exhaustion. They find several genes related to epigenetic modification and show that by eliminating Arid1a, CD8+ T cells retain proliferative and cytotoxic function in vivo, leading to better anti-tumor activity.
    DOI:  https://doi.org/10.1016/j.ccell.2022.06.008
  22. Front Immunol. 2022 ;13 909270
    Fra-2 Is a Dominant Negative Regulator of Natural Killer Cell Development.
    Diana Schnoegl, Mathias Hochgerner, Dagmar Gotthardt, Leigh M Marsh.
      Natural killer (NK) cells play an important role in recognizing and killing pathogen-infected or malignant cells. Changes in their numbers or activation can contribute to several diseases and pathologies including systemic sclerosis (SSc), an autoimmune disease characterized by inflammation and tissue remodeling. In these patients, increased expression of the AP-1 transcription factor, Fra-2 was reported. In mice ectopic overexpression of Fra-2 (TG) leads to SSc with strong pulmonary fibrosis, pulmonary hypertension, and inflammation. Analysis of the underlying immune cell profile in the lungs of young TG mice, which do not yet show any signs of lung disease, revealed increased numbers of eosinophils and T cells but strongly reduced NK numbers. Therefore, we aimed to identify the cause of the absence of NK cells in the lungs of these mice and to determine the potential role of Fra-2 in NK development. Examination of inflammatory cell distribution in TG mice revealed similar NK deficiencies in the spleen, blood, and bone marrow. Deeper analysis of the WT and TG bone marrow revealed a potential NK cell developmental defect beginning at the preNKP stage. To determine whether this defect was cell-intrinsic or extrinsic, mixed bone marrow chimera and in vitro differentiation experiments were performed. Both experiments showed that the defect caused by Fra-2 was primarily cell-intrinsic and minimally dependent on the environment. Closer examination of surface markers and transcription factors required for NK development, revealed the expected receptor distribution but changes in transcription factor expression. We found a significant reduction in Nfil3, which is essential for the transition of common lymphoid cells to NK committed precursor cells and an AP-1 binding site in the promotor of this gene. In Summary, our data demonstrates that regulation of Fra-2 is essential for NK development and maturation, and suggests that the early NK dysfunction plays an important role in the pathogenesis of systemic sclerosis.
    Keywords:  AP-1; Fra-2; Natural killer (NK) cell; activator protein 1; differentiation; innate immunity
    DOI:  https://doi.org/10.3389/fimmu.2022.909270
  23. Mucosal Immunol. 2022 Jul 11.
    Mucosal viral infection induces a regulatory T cell activation phenotype distinct from tissue residency in mouse and human tissues.
    Brianna Traxinger, Sarah C Vick, Amanda Woodward-Davis, Valentin Voillet, Jami R Erickson, Julie Czartoski, Candice Teague, Martin Prlic, Jennifer M Lund.
      Regulatory T cells (Tregs) mediate immune homeostasis, yet also facilitate nuanced immune responses during infection, balancing pathogen control while limiting host inflammation. Recent studies have identified Treg populations in non-lymphoid tissues that are phenotypically distinct from Tregs in lymphoid tissues (LT), including performance of location-dependent roles. Mucosal tissues serve as critical barriers to microbes while performing unique physiologic functions, so we sought to identify distinct phenotypical and functional aspects of mucosal Tregs in the female reproductive tract. In healthy human and mouse vaginal mucosa, we found that Tregs are highly activated compared to blood or LT Tregs. To determine if this phenotype reflects acute activation or a general signature of vaginal tract (VT)-residency, we infected mice with HSV-2 to discover that VT Tregs express granzyme-B (GzmB) and acquire a VT Treg signature distinct from baseline. To determine the mechanisms that drive GzmB expression, we performed ex vivo assays to reveal that a combination of type-I interferons and interleukin-2 is sufficient for GzmB expression. Together, we highlight that VT Tregs are activated at steady state and become further activated in response to infection; thus, they may exert robust control of local immune responses, which could have implications for mucosal vaccine design.
    DOI:  https://doi.org/10.1038/s41385-022-00542-7
  24. Nat Commun. 2022 Jul 11. 13(1): 4020
    Nestin-dependent mitochondria-ER contacts define stem Leydig cell differentiation to attenuate male reproductive ageing.
    Senyu Yao, Xiaoyue Wei, Wenrui Deng, Boyan Wang, Jianye Cai, Yinong Huang, Xiaofan Lai, Yuan Qiu, Yi Wang, Yuanjun Guan, Jiancheng Wang.
      Male reproductive system ageing is closely associated with deficiency in testosterone production due to loss of functional Leydig cells, which are differentiated from stem Leydig cells (SLCs). However, the relationship between SLC differentiation and ageing remains unknown. In addition, active lipid metabolism during SLC differentiation in the reproductive system requires transportation and processing of substrates among multiple organelles, e.g., mitochondria and endoplasmic reticulum (ER), highlighting the importance of interorganelle contact. Here, we show that SLC differentiation potential declines with disordered intracellular homeostasis during SLC senescence. Mechanistically, loss of the intermediate filament Nestin results in lower differentiation capacity by separating mitochondria-ER contacts (MERCs) during SLC senescence. Furthermore, pharmacological intervention by melatonin restores Nestin-dependent MERCs, reverses SLC differentiation capacity and alleviates male reproductive system ageing. These findings not only explain SLC senescence from a cytoskeleton-dependent MERCs regulation mechanism, but also suggest a promising therapy targeting SLC differentiation for age-related reproductive system diseases.
    DOI:  https://doi.org/10.1038/s41467-022-31755-w
  25. Nat Genet. 2022 Jul;54(7): 940-949
    A sequence-based global map of regulatory activity for deciphering human genetics.
    Kathleen M Chen, Aaron K Wong, Olga G Troyanskaya, Jian Zhou.
      Epigenomic profiling has enabled large-scale identification of regulatory elements, yet we still lack a systematic mapping from any sequence or variant to regulatory activities. We address this challenge with Sei, a framework for integrating human genetics data with sequence information to discover the regulatory basis of traits and diseases. Sei learns a vocabulary of regulatory activities, called sequence classes, using a deep learning model that predicts 21,907 chromatin profiles across >1,300 cell lines and tissues. Sequence classes provide a global classification and quantification of sequence and variant effects based on diverse regulatory activities, such as cell type-specific enhancer functions. These predictions are supported by tissue-specific expression, expression quantitative trait loci and evolutionary constraint data. Furthermore, sequence classes enable characterization of the tissue-specific, regulatory architecture of complex traits and generate mechanistic hypotheses for individual regulatory pathogenic mutations. We provide Sei as a resource to elucidate the regulatory basis of human health and disease.
    DOI:  https://doi.org/10.1038/s41588-022-01102-2
  26. Trends Genet. 2022 Jul 07. pii: S0168-9525(22)00141-X. [Epub ahead of print]
    Transcriptional enhancers at 40: evolution of a viral DNA element to nuclear architectural structures.
    Sreejith J Nair, Tom Suter, Susan Wang, Lu Yang, Feng Yang, Michael G Rosenfeld.
      Gene regulation by transcriptional enhancers is the dominant mechanism driving cell type- and signal-specific transcriptional diversity in metazoans. However, over four decades since the original discovery, how enhancers operate in the nuclear space remains largely enigmatic. Recent multidisciplinary efforts combining real-time imaging, genome sequencing, and biophysical strategies provide insightful but conflicting models of enhancer-mediated gene control. Here, we review the discovery and progress in enhancer biology, emphasizing the recent findings that acutely activated enhancers assemble regulatory machinery as mesoscale architectural structures with distinct physical properties. These findings help formulate novel models that explain several mysterious features of the assembly of transcriptional enhancers and the mechanisms of spatial control of gene expression.
    Keywords:  condensates; eRNA; enhancers; gene regulation; intrinsically disordered regions (IDRs); noncoding genome
    DOI:  https://doi.org/10.1016/j.tig.2022.05.015
  27. Nat Commun. 2022 Jul 14. 13(1): 4096
    Microglia coordinate cellular interactions during spinal cord repair in mice.
    Faith H Brennan, Yang Li, Cankun Wang, Anjun Ma, Qi Guo, Yi Li, Nicole Pukos, Warren A Campbell, Kristina G Witcher, Zhen Guan, Kristina A Kigerl, Jodie C E Hall, Jonathan P Godbout, Andy J Fischer, Dana M McTigue, Zhigang He, Qin Ma, Phillip G Popovich.
      Traumatic spinal cord injury (SCI) triggers a neuro-inflammatory response dominated by tissue-resident microglia and monocyte derived macrophages (MDMs). Since activated microglia and MDMs are morphologically identical and express similar phenotypic markers in vivo, identifying injury responses specifically coordinated by microglia has historically been challenging. Here, we pharmacologically depleted microglia and use anatomical, histopathological, tract tracing, bulk and single cell RNA sequencing to reveal the cellular and molecular responses to SCI controlled by microglia. We show that microglia are vital for SCI recovery and coordinate injury responses in CNS-resident glia and infiltrating leukocytes. Depleting microglia exacerbates tissue damage and worsens functional recovery. Conversely, restoring select microglia-dependent signaling axes, identified through sequencing data, in microglia depleted mice prevents secondary damage and promotes recovery. Additional bioinformatics analyses reveal that optimal repair after SCI might be achieved by co-opting key ligand-receptor interactions between microglia, astrocytes and MDMs.
    DOI:  https://doi.org/10.1038/s41467-022-31797-0
  28. Cell Metab. 2022 Jul 07. pii: S1550-4131(22)00228-5. [Epub ahead of print]
    Tumor cells dictate anti-tumor immune responses by altering pyruvate utilization and succinate signaling in CD8+ T cells.
    Ilaria Elia, Jared H Rowe, Sheila Johnson, Shakchhi Joshi, Giulia Notarangelo, Kiran Kurmi, Sarah Weiss, Gordon J Freeman, Arlene H Sharpe, Marcia C Haigis.
      The tumor microenvironment (TME) is a unique metabolic niche that can inhibit T cell metabolism and cytotoxicity. To dissect the metabolic interplay between tumors and T cells, we establish an in vitro system that recapitulates the metabolic niche of the TME and allows us to define cell-specific metabolism. We identify tumor-derived lactate as an inhibitor of CD8+ T cell cytotoxicity, revealing an unexpected metabolic shunt in the TCA cycle. Metabolically fit cytotoxic T cells shunt succinate out of the TCA cycle to promote autocrine signaling via the succinate receptor (SUCNR1). Cytotoxic T cells are reliant on pyruvate carboxylase (PC) to replenish TCA cycle intermediates. By contrast, lactate reduces PC-mediated anaplerosis. The inhibition of pyruvate dehydrogenase (PDH) is sufficient to restore PC activity, succinate secretion, and the activation of SUCNR1. These studies identify PDH as a potential drug target to allow CD8+ T cells to retain cytotoxicity and overcome a lactate-enriched TME.
    Keywords:  T cells; cancer metabolism; lactate; pyruvate; succinate; tumor immunity
    DOI:  https://doi.org/10.1016/j.cmet.2022.06.008
  29. Mucosal Immunol. 2022 Jul 09.
    Neuromedin U promotes human type 2 immune responses.
    Yuan Ye, Jian Luo, Ni Zeng, Shan Jiang, Wentao Chen, Ryan D Hoyle, Paul Klenerman, Ian D Pavord, Luzheng Xue.
      Type 2 immunity mediates the immune responses against parasites and allergic stimuli. Evidence from studies of cell lines and animals implies that neuromedin U (NmU) acts as a pro-inflammatory mediator of type 2 inflammation. However, the role of NmU in human type 2 immunity remains unclear. Here we investigated the expression of NmU in human blood and airways, and the expression of NmU receptors by human immune cells in blood and lung tissue. We detected human NmU (hNmU-25) in blood and airways with higher concentrations in the latter. NmU receptor 1 (NmUR1) was expressed by most human immune cells with higher levels in type 2 cells including type 2 T helpers, type 2 cytotoxic T cells, group-2 innate lymphoid cells and eosinophils, and was upregulated in lung-resident and activated type 2 cells. We also assessed the effects of NmU in these cells. hNmU-25 elicited type 2 cytokine production by type 2 lymphocytes and induced cell migration, including eosinophils. hNmU-25 also enhanced the type 2 immune response to other stimuli, particularly prostaglandin D2. These results indicate that NmU could contribute to the pathogenic processes of type 2 immunity-mediated diseases in humans via its pro-inflammatory effects on type 2 lymphocytes and eosinophils.
    DOI:  https://doi.org/10.1038/s41385-022-00543-6
  30. Nature. 2022 Jul 13.
    Within-host evolution of a gut pathobiont facilitates liver translocation.
    Yi Yang, Mytien Nguyen, Varnica Khetrapal, Nicole D Sonnert, Anjelica L Martin, Haiwei Chen, Martin A Kriegel, Noah W Palm.
      Gut commensal bacteria with the ability to translocate across the intestinal barrier can drive the development of diverse immune-mediated diseases1-4. However, the key factors that dictate bacterial translocation remain unclear. Recent studies have revealed that gut microbiota strains can adapt and evolve throughout the lifetime of the host5-9, raising the possibility that changes in individual commensal bacteria themselves over time may affect their propensity to elicit inflammatory disease. Here we show that within-host evolution of the model gut pathobiont Enterococcus gallinarum facilitates bacterial translocation and initiation of inflammation. Using a combination of in vivo experimental evolution and comparative genomics, we found that E. gallinarum diverges into independent lineages adapted to colonize either luminal or mucosal niches in the gut. Compared with ancestral and luminal E. gallinarum, mucosally adapted strains evade detection and clearance by the immune system, exhibit increased translocation to and survival within the mesenteric lymph nodes and liver, and induce increased intestinal and hepatic inflammation. Mechanistically, these changes in bacterial behaviour are associated with non-synonymous mutations or insertion-deletions in defined regulatory genes in E. gallinarum, altered microbial gene expression programs and remodelled cell wall structures. Lactobacillus reuteri also exhibited broadly similar patterns of divergent evolution and enhanced immune evasion in a monocolonization-based model of within-host evolution. Overall, these studies define within-host evolution as a critical regulator of commensal pathogenicity that provides a unique source of stochasticity in the development and progression of microbiota-driven disease.
    DOI:  https://doi.org/10.1038/s41586-022-04949-x
  31. Curr Opin Genet Dev. 2022 Jul 08. pii: S0959-437X(22)00064-8. [Epub ahead of print]75 101955
    Brain organoids: the quest to decipher human-specific features of brain development.
    Ana Uzquiano, Paola Arlotta.
      The development of the human brain occurs largely in utero over long periods of time and is thus experimentally inaccessible; therefore, tractable experimental models are needed. Human brain organoid have emerged as powerful model systems to investigate human-specific features of brain development. Focusing on the cerebral cortex, here, we discuss how brain, and more specifically cortical, organoid models have newly enabled discovery of aspects of progenitor biology and cortical-cell diversification that are unique to humans. We foresee that as advancements in organoid generation increase the complexity of these models, more complete replicas of the brain will empower future studies investigating higher-order aspects of brain biology, toward an understanding of the unique processing capabilities of the human brain.
    DOI:  https://doi.org/10.1016/j.gde.2022.101955
  32. Nat Commun. 2022 Jul 09. 13(1): 3999
    Programmable CRISPR-Cas9 microneedle patch for long-term capture and real-time monitoring of universal cell-free DNA.
    Bin Yang, Jilie Kong, Xueen Fang.
      Recent advances in biointerfaces have led to the development of wearable devices that can provide insights into personal health. As wearable modules, microneedles can extract analytes of interest from interstitial fluid in a minimally invasive fashion. However, some microneedles are limited by their ability to perform highly effective extraction and real-time monitoring for macromolecule biomarkers simultaneously. Here we show the synergetic effect of CRISPR-activated graphene biointerfaces, and report an on-line wearable microneedle patch for extraction and in vivo long-term monitoring of universal cell-free DNA. In this study, this wearable system enables real-time monitoring of Epstein-Barr virus, sepsis, and kidney transplantation cell-free DNA, with anti-interference ability of 60% fetal bovine serum, and has satisfactory stable sensitivity for 10 days in vivo. The experimental results of immunodeficient mouse models shows the feasibility and practicability of this proposed method. This wearable patch holds great promise for long-term in vivo monitoring of cell-free DNA and could potentially be used for early disease screening and prognosis.
    DOI:  https://doi.org/10.1038/s41467-022-31740-3
  33. Nature. 2022 Jul 14.
    How do thin people stay that way? More activity is not always the answer.
      
    Keywords:  Metabolism
    DOI:  https://doi.org/10.1038/d41586-022-01909-3
  34. Nat Commun. 2022 Jul 14. 13(1): 4084
    Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism.
    Yoon Keun Cho, Young Cheol Yoon, Hyeonyeong Im, Yeonho Son, Minsu Kim, Abhirup Saha, Cheoljun Choi, Jaewon Lee, Sumin Lee, Jae Hyun Kim, Yun Pyo Kang, Young-Suk Jung, Hong Koo Ha, Je Kyung Seong, James G Granneman, Sung Won Kwon, Yun-Hee Lee.
      Dysregulation of adipose tissue plasmalogen metabolism is associated with obesity-related metabolic diseases. We report that feeding mice a high-fat diet reduces adipose tissue lysoplasmalogen levels and increases transmembrane protein 86 A (TMEM86A), a putative lysoplasmalogenase. Untargeted lipidomic analysis demonstrates that adipocyte-specific TMEM86A-knockout (AKO) increases lysoplasmalogen content in adipose tissue, including plasmenyl lysophosphatidylethanolamine 18:0 (LPE P-18:0). Surprisingly, TMEM86A AKO increases protein kinase A signalling pathways owing to inhibition of phosphodiesterase 3B and elevation of cyclic adenosine monophosphate. TMEM86A AKO upregulates mitochondrial oxidative metabolism, elevates energy expenditure, and protects mice from metabolic dysfunction induced by high-fat feeding. Importantly, the effects of TMEM86A AKO are largely reproduced in vitro and in vivo by LPE P-18:0 supplementation. LPE P-18:0 levels are significantly lower in adipose tissue of human patients with obesity, suggesting that TMEM86A inhibition or lysoplasmalogen supplementation might be therapeutic approaches for preventing or treating obesity-related metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-022-31805-3
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