bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022‒06‒12
fifty-nine papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. Integrative epigenomic and transcriptomic analysis reveals the requirement of JUNB for hematopoietic fate induction.
  2. Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2.
  3. Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity.
  4. Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.
  5. Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis.
  6. Itaconate is a lysosomal inducer that promotes antibacterial innate immunity.
  7. Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure.
  8. Unraveling function and diversity of bacterial lectins in the human microbiome.
  9. An in vitro model of neuronal ensembles.
  10. Impaired humoral immunity is associated with prolonged COVID-19 despite robust CD8 T cell responses.
  11. Potentiating adoptive cell therapy using synthetic IL-9 receptors.
  12. Targeting thalamic circuits rescues motor and mood deficits in PD mice.
  13. Exploring the cellular landscape of circular RNAs using full-length single-cell RNA sequencing.
  14. Mafa-dependent GABAergic activity promotes mouse neonatal apneas.
  15. The mammalian SKIV2L RNA exosome is essential for early B cell development.
  16. Variant to function mapping at single-cell resolution through network propagation.
  17. Sirt6-mediated epigenetic modification of DNA accessibility is essential for Pou2f3-induced thymic tuft cell development.
  18. Taf2 mediates DNA binding of Taf14.
  19. Control of CRK-RAC1 activity by the miR-1/206/133 miRNA family is essential for neuromuscular junction function.
  20. Norepinephrine potentiates and serotonin depresses visual cortical responses by transforming eligibility traces.
  21. JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation.
  22. Structural basis for MTA1c-mediated DNA N6-adenine methylation.
  23. Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET.
  24. Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity.
  25. Comprehensive identification of SWI/SNF complex subunits underpins deep eukaryotic ancestry and reveals new plant components.
  26. Ex vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis.
  27. A preoptic neuronal population controls fever and appetite during sickness.
  28. Efferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity.
  29. Immune monitoring and treatment in immune-mediated inflammatory diseases.
  30. Cohesin-mediated loop anchors confine the locations of human replication origins.
  31. High resolution microfluidic assay and probabilistic modeling reveal cooperation between T cells in tumor killing.
  32. A surprise in the eye: long-lived T cells patrol the cornea.
  33. RNA exosome drives early B cell development via noncoding RNA processing mechanisms.
  34. Molecular basis of mEAK7-mediated human V-ATPase regulation.
  35. Nuclear RIPK1 promotes chromatin remodeling to mediate inflammatory response.
  36. Hippocampal representations switch from errors to predictions during acquisition of predictive associations.
  37. Profiling Fusobacterium infection at high taxonomic resolution reveals lineage-specific correlations in colorectal cancer.
  38. Normalization of maternal adiponectin in obese pregnant mice prevents programming of impaired glucose metabolism in adult offspring.
  39. Dynamic nucleosome landscape elicits a noncanonical GATA2 pioneer model.
  40. Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation.
  41. Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL.
  42. Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity.
  43. Serotonin and dopamine modulate aging in response to food odor and availability.
  44. The spatiotemporal program of zonal liver regeneration following acute injury.
  45. NuRD complex recruitment to Thpok mediates CD4+ T cell lineage differentiation.
  46. Lysosome lipid signalling from the periphery to neurons regulates longevity.
  47. Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis.
  48. Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia.
  49. Linking task structure and neural network dynamics.
  50. Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome.
  51. tRNA dysregulation and disease.
  52. Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes.
  53. Proteomic and functional analyses of the periodic membrane skeleton in neurons.
  54. CRISPR comes a-knock-in to reprogram antibodies in vivo.
  55. Myths about diversity in clinical trials reduce return on investment for industry.
  56. GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.
  57. Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data.
  58. Mitochondrial reactive oxygen is critical for IL-12/IL-18-induced IFN-γ production by CD4+ T cells and is regulated by Fas/FasL signaling.
  59. Single-cell RNA sequencing sheds light on cell-type specific gene expression in immune cells.
  1. Nat Commun. 2022 Jun 06. 13(1): 3131
    Integrative epigenomic and transcriptomic analysis reveals the requirement of JUNB for hematopoietic fate induction.
    Xia Chen, Peiliang Wang, Hui Qiu, Yonglin Zhu, Xingwu Zhang, Yaxuan Zhang, Fuyu Duan, Shuangyuan Ding, Jianying Guo, Yue Huang, Jie Na.
      Human pluripotent stem cell differentiation towards hematopoietic progenitor cell can serve as an in vitro model for human embryonic hematopoiesis, but the dynamic change of epigenome and transcriptome remains elusive. Here, we systematically profile the chromatin accessibility, H3K4me3 and H3K27me3 modifications, and the transcriptome of intermediate progenitors during hematopoietic progenitor cell differentiation in vitro. The integrative analyses reveal sequential opening-up of regions for the binding of hematopoietic transcription factors and stepwise epigenetic reprogramming of bivalent genes. Single-cell analysis of cells undergoing the endothelial-to-hematopoietic transition and comparison with in vivo hemogenic endothelial cells reveal important features of in vitro and in vivo hematopoiesis. We find that JUNB is an essential regulator for hemogenic endothelium specialization and endothelial-to-hematopoietic transition. These studies depict an epigenomic roadmap from human pluripotent stem cells to hematopoietic progenitor cells, which may pave the way to generate hematopoietic progenitor cells with improved developmental potentials.
    DOI:  https://doi.org/10.1038/s41467-022-30789-4
  2. Nat Commun. 2022 Jun 06. 13(1): 3250
    Omicron-specific mRNA vaccination alone and as a heterologous booster against SARS-CoV-2.
    Zhenhao Fang, Lei Peng, Renata Filler, Kazushi Suzuki, Andrew McNamara, Qianqian Lin, Paul A Renauer, Luojia Yang, Bridget Menasche, Angie Sanchez, Ping Ren, Qiancheng Xiong, Madison Strine, Paul Clark, Chenxiang Lin, Albert I Ko, Nathan D Grubaugh, Craig B Wilen, Sidi Chen.
      The Omicron variant of SARS-CoV-2 recently swept the globe and showed high level of immune evasion. Here, we generate an Omicron-specific lipid nanoparticle (LNP) mRNA vaccine candidate, and test its activity in animals, both alone and as a heterologous booster to WT mRNA vaccine. Our Omicron-specific LNP-mRNA vaccine elicits strong antibody response in vaccination-naïve mice. Mice that received two-dose WT LNP-mRNA show a > 40-fold reduction in neutralization potency against Omicron than WT two weeks post boost, which further reduce to background level after 3 months. The WT or Omicron LNP-mRNA booster increases the waning antibody response of WT LNP-mRNA vaccinated mice against Omicron by 40 fold at two weeks post injection. Interestingly, the heterologous Omicron booster elicits neutralizing titers 10-20 fold higher than the homologous WT booster against Omicron variant, with comparable titers against Delta variant. All three types of vaccination, including Omicron alone, WT booster and Omicron booster, elicit broad binding antibody responses against SARS-CoV-2 WA-1, Beta, Delta variants and SARS-CoV. These data provide direct assessments of an Omicron-specific mRNA vaccination in vivo, both alone and as a heterologous booster to WT mRNA vaccine.
    DOI:  https://doi.org/10.1038/s41467-022-30878-4
  3. Nat Commun. 2022 Jun 09. 13(1): 3222
    Mechanically active integrins target lytic secretion at the immune synapse to facilitate cellular cytotoxicity.
    Mitchell S Wang, Yuesong Hu, Elisa E Sanchez, Xihe Xie, Nathan H Roy, Miguel de Jesus, Benjamin Y Winer, Elizabeth A Zale, Weiyang Jin, Chirag Sachar, Joanne H Lee, Yeonsun Hong, Minsoo Kim, Lance C Kam, Khalid Salaita, Morgan Huse.
      Cytotoxic lymphocytes fight pathogens and cancer by forming immune synapses with infected or transformed target cells and then secreting cytotoxic perforin and granzyme into the synaptic space, with potent and specific killing achieved by this focused delivery. The mechanisms that establish the precise location of secretory events, however, remain poorly understood. Here we use single cell biophysical measurements, micropatterning, and functional assays to demonstrate that localized mechanotransduction helps define the position of secretory events within the synapse. Ligand-bound integrins, predominantly the αLβ2 isoform LFA-1, function as spatial cues to attract lytic granules containing perforin and granzyme and induce their fusion with the plasma membrane for content release. LFA-1 is subjected to pulling forces within secretory domains, and disruption of these forces via depletion of the adaptor molecule talin abrogates cytotoxicity. We thus conclude that lymphocytes employ an integrin-dependent mechanical checkpoint to enhance their cytotoxic power and fidelity.
    DOI:  https://doi.org/10.1038/s41467-022-30809-3
  4. Cell. 2022 Jun 02. pii: S0092-8674(22)00597-9. [Epub ahead of print]
    Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq.
    Joseph M Replogle, Reuben A Saunders, Angela N Pogson, Jeffrey A Hussmann, Alexander Lenail, Alina Guna, Lauren Mascibroda, Eric J Wagner, Karen Adelman, Gila Lithwick-Yanai, Nika Iremadze, Florian Oberstrass, Doron Lipson, Jessica L Bonnar, Marco Jost, Thomas M Norman, Jonathan S Weissman.
      A central goal of genetics is to define the relationships between genotypes and phenotypes. High-content phenotypic screens such as Perturb-seq (CRISPR-based screens with single-cell RNA-sequencing readouts) enable massively parallel functional genomic mapping but, to date, have been used at limited scales. Here, we perform genome-scale Perturb-seq targeting all expressed genes with CRISPR interference (CRISPRi) across >2.5 million human cells. We use transcriptional phenotypes to predict the function of poorly characterized genes, uncovering new regulators of ribosome biogenesis (including CCDC86, ZNF236, and SPATA5L1), transcription (C7orf26), and mitochondrial respiration (TMEM242). In addition to assigning gene function, single-cell transcriptional phenotypes allow for in-depth dissection of complex cellular phenomena-from RNA processing to differentiation. We leverage this ability to systematically identify genetic drivers and consequences of aneuploidy and to discover an unanticipated layer of stress-specific regulation of the mitochondrial genome. Our information-rich genotype-phenotype map reveals a multidimensional portrait of gene and cellular function.
    Keywords:  CRISPR; Integrator complex; Perturb-seq; cell biology; chromosomal instability; genetic screens; genotype-phenotype map; mitochondrial genome stress response; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.cell.2022.05.013
  5. Nat Commun. 2022 Jun 06. 13(1): 3140
    Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis.
    William Damsky, Alice Wang, Daniel J Kim, Bryan D Young, Katelyn Singh, Michael J Murphy, Joseph Daccache, Abigale Clark, Ruveyda Ayasun, Changwan Ryu, Meaghan K McGeary, Ian D Odell, Ramesh Fazzone-Chettiar, Darko Pucar, Robert Homer, Mridu Gulati, Edward J Miller, Marcus Bosenberg, Richard A Flavell, Brett King.
      Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4+ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.
    DOI:  https://doi.org/10.1038/s41467-022-30615-x
  6. Mol Cell. 2022 May 25. pii: S1097-2765(22)00443-9. [Epub ahead of print]
    Itaconate is a lysosomal inducer that promotes antibacterial innate immunity.
    Zhenxing Zhang, Chao Chen, Fan Yang, Yi-Xin Zeng, Pengkai Sun, Ping Liu, Xinjian Li.
      Lysosomes are the main organelles in macrophages for killing invading bacteria. However, the precise mechanism underlying lysosomal biogenesis upon bacterial infection remains enigmatic. We demonstrate here that LPS stimulation increases IRG1-dependent itaconate production, which promotes lysosomal biogenesis by activating the transcription factor, TFEB. Mechanistically, itaconate directly alkylates human TFEB at cysteine 212 (Cys270 in mice) to induce its nuclear localization by antagonizing mTOR-mediated phosphorylation and cytosolic retention. Functionally, abrogation of itaconate synthesis by IRG1/Irg1 knockout or expression of an alkylation-deficient TFEB mutant impairs the antibacterial ability of macrophages in vitro. Furthermore, knockin mice harboring an alkylation-deficient TFEB mutant display elevated susceptibility to Salmonella typhimurium infection, whereas in vivo treatment of OI, a cell-permeable itaconate derivative, limits inflammation. Our study identifies itaconate as an endogenous metabolite that functions as a lysosomal inducer in macrophages in response to bacterial infection, implying the potential therapeutic utility of itaconate in treating human bacterial infection.
    Keywords:  TFEB; alkylation; bacterial infection; innate immunity; itaconate; lysosomal biogenesis; macrophage
    DOI:  https://doi.org/10.1016/j.molcel.2022.05.009
  7. Nat Commun. 2022 Jun 07. 13(1): 3267
    Single-cell RNA-sequencing of peripheral blood mononuclear cells reveals widespread, context-specific gene expression regulation upon pathogenic exposure.
    single-cell eQTLGen consortium
      The host's gene expression and gene regulatory response to pathogen exposure can be influenced by a combination of the host's genetic background, the type of and exposure time to pathogens. Here we provide a detailed dissection of this using single-cell RNA-sequencing of 1.3M peripheral blood mononuclear cells from 120 individuals, longitudinally exposed to three different pathogens. These analyses indicate that cell-type-specificity is a more prominent factor than pathogen-specificity regarding contexts that affect how genetics influences gene expression (i.e., eQTL) and co-expression (i.e., co-expression QTL). In monocytes, the strongest responder to pathogen stimulations, 71.4% of the genetic variants whose effect on gene expression is influenced by pathogen exposure (i.e., response QTL) also affect the co-expression between genes. This indicates widespread, context-specific changes in gene expression level and its regulation that are driven by genetics. Pathway analysis on the CLEC12A gene that exemplifies cell-type-, exposure-time- and genetic-background-dependent co-expression interactions, shows enrichment of the interferon (IFN) pathway specifically at 3-h post-exposure in monocytes. Similar genetic background-dependent association between IFN activity and CLEC12A co-expression patterns is confirmed in systemic lupus erythematosus by in silico analysis, which implies that CLEC12A might be an IFN-regulated gene. Altogether, this study highlights the importance of context for gaining a better understanding of the mechanisms of gene regulation in health and disease.
    DOI:  https://doi.org/10.1038/s41467-022-30893-5
  8. Nat Commun. 2022 Jun 03. 13(1): 3101
    Unraveling function and diversity of bacterial lectins in the human microbiome.
    Louis J Cohen, Sun M Han, Pearson Lau, Daniela Guisado, Yupu Liang, Toshiki G Nakashige, Thamina Ali, David Chiang, Adeeb Rahman, Sean F Brady.
      The mechanisms by which commensal organisms affect human physiology remain poorly understood. Lectins are non-enzymatic carbohydrate binding proteins that all organisms employ as part of establishing a niche, evading host-defenses and protecting against pathogens. Although lectins have been extensively studied in plants, bacterial pathogens and human immune cells for their role in disease pathophysiology and as therapeutics, the role of bacterial lectins in the human microbiome is largely unexplored. Here we report on the characterization of a lectin produced by a common human associated bacterium that interacts with myeloid cells in the blood and intestine. In mouse and cell-based models, we demonstrate that this lectin induces distinct immunologic responses in peripheral and intestinal leukocytes and that these responses are specific to monocytes, macrophages and dendritic cells. Our analysis of human microbiota sequencing data reveal thousands of unique sequences that are predicted to encode lectins, many of which are highly prevalent in the human microbiome yet completely uncharacterized. Based on the varied domain architectures of these lectins we predict they will have diverse effects on the human host. The systematic investigation of lectins in the human microbiome should improve our understanding of human health and provide new therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41467-022-29949-3
  9. Nat Commun. 2022 Jun 09. 13(1): 3340
    An in vitro model of neuronal ensembles.
    M Angeles Rabadan, Estanislao Daniel De La Cruz, Sneha B Rao, Yannan Chen, Cheng Gong, Gregg Crabtree, Bin Xu, Sander Markx, Joseph A Gogos, Rafael Yuste, Raju Tomer.
      Advances in 3D neuronal cultures, such as brain spheroids and organoids, are allowing unprecedented in vitro access to some of the molecular, cellular and developmental mechanisms underlying brain diseases. However, their efficacy in recapitulating brain network properties that encode brain function remains limited, thereby precluding development of effective in vitro models of complex brain disorders like schizophrenia. Here, we develop and characterize a Modular Neuronal Network (MoNNet) approach that recapitulates specific features of neuronal ensemble dynamics, segregated local-global network activities and a hierarchical modular organization. We utilized MoNNets for quantitative in vitro modelling of schizophrenia-related network dysfunctions caused by highly penetrant mutations in SETD1A and 22q11.2 risk loci. Furthermore, we demonstrate its utility for drug discovery by performing pharmacological rescue of alterations in neuronal ensembles stability and global network synchrony. MoNNets allow in vitro modelling of brain diseases for investigating the underlying neuronal network mechanisms and systematic drug discovery.
    DOI:  https://doi.org/10.1038/s41467-022-31073-1
  10. Cancer Cell. 2022 May 30. pii: S1535-6108(22)00226-4. [Epub ahead of print]
    Impaired humoral immunity is associated with prolonged COVID-19 despite robust CD8 T cell responses.
    Olga Lyudovyk, Justin Y Kim, David Qualls, Madeline A Hwee, Ya-Hui Lin, Sawsan R Boutemine, Yuval Elhanati, Alexander Solovyov, Melanie Douglas, Eunise Chen, N Esther Babady, Lakshmi Ramanathan, Pallavi Vedantam, Chaitanya Bandlamudi, Sigrid Gouma, Philip Wong, Scott E Hensley, Benjamin Greenbaum, Alexander C Huang, Santosha A Vardhana.
      How immune dysregulation affects recovery from COVID-19 infection in patients with cancer remains unclear. We analyzed cellular and humoral immune responses in 103 patients with prior COVID-19 infection, more than 20% of whom had delayed viral clearance. Delayed clearance was associated with loss of antibodies to nucleocapsid and spike proteins with a compensatory increase in functional T cell responses. High-dimensional analysis of peripheral blood samples demonstrated increased CD8+ effector T cell differentiation and a broad but poorly converged COVID-specific T cell receptor (TCR) repertoire in patients with prolonged disease. Conversely, patients with a CD4+ dominant immunophenotype had a lower incidence of prolonged disease and exhibited a deep and highly select COVID-associated TCR repertoire, consistent with effective viral clearance and development of T cell memory. These results highlight the importance of B cells and CD4+ T cells in promoting durable SARS-CoV-2 clearance and the significance of coordinated cellular and humoral immunity for long-term disease control.
    Keywords:  CD20; COVID-19; SARS-CoV-2; T cell; cancer; convalescent; rituximab
    DOI:  https://doi.org/10.1016/j.ccell.2022.05.013
  11. Nature. 2022 Jun 08.
    Potentiating adoptive cell therapy using synthetic IL-9 receptors.
    Anusha Kalbasi, Mikko Siurala, Leon L Su, Mito Tariveranmoshabad, Lora K Picton, Pranali Ravikumar, Peng Li, Jian-Xin Lin, Helena Escuin-Ordinas, Tong Da, Sarah V Kremer, Amy L Sun, Sofia Castelli, Sangya Agarwal, John Scholler, Decheng Song, Philipp C Rommel, Enrico Radaelli, Regina M Young, Warren J Leonard, Antoni Ribas, Carl H June, K Christopher Garcia.
      Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γc) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γc cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD-IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.
    DOI:  https://doi.org/10.1038/s41586-022-04801-2
  12. Nature. 2022 Jun 08.
    Targeting thalamic circuits rescues motor and mood deficits in PD mice.
    Ying Zhang, Dheeraj S Roy, Yi Zhu, Yefei Chen, Tomomi Aida, Yuanyuan Hou, Chenjie Shen, Nicholas E Lea, Margaret E Schroeder, Keith M Skaggs, Heather A Sullivan, Kyle B Fischer, Edward M Callaway, Ian R Wickersham, Ji Dai, Xiao-Ming Li, Zhonghua Lu, Guoping Feng.
      Although bradykinesia, tremor and rigidity are the hallmark motor defects in patients with Parkinson's disease (PD), patients also experience motor learning impairments and non-motor symptoms such as depression1. The neural circuit basis for these different symptoms of PD are not well understood. Although current treatments are effective for locomotion deficits in PD2,3, therapeutic strategies targeting motor learning deficits and non-motor symptoms are lacking4-6. Here we found that distinct parafascicular (PF) thalamic subpopulations project to caudate putamen (CPu), subthalamic nucleus (STN) and nucleus accumbens (NAc). Whereas PF→CPu and PF→STN circuits are critical for locomotion and motor learning, respectively, inhibition of the PF→NAc circuit induced a depression-like state. Whereas chemogenetically manipulating CPu-projecting PF neurons led to a long-term restoration of locomotion, optogenetic long-term potentiation (LTP) at PF→STN synapses restored motor learning behaviour in an acute mouse model of PD. Furthermore, activation of NAc-projecting PF neurons rescued depression-like phenotypes. Further, we identified nicotinic acetylcholine receptors capable of modulating PF circuits to rescue different PD phenotypes. Thus, targeting PF thalamic circuits may be an effective strategy for treating motor and non-motor deficits in PD.
    DOI:  https://doi.org/10.1038/s41586-022-04806-x
  13. Nat Commun. 2022 Jun 10. 13(1): 3242
    Exploring the cellular landscape of circular RNAs using full-length single-cell RNA sequencing.
    Wanying Wu, Jinyang Zhang, Xiaofei Cao, Zhengyi Cai, Fangqing Zhao.
      Previous studies have demonstrated the highly specific expression of circular RNAs (circRNAs) in different tissues and organisms, but the cellular architecture of circRNA has never been fully characterized. Here, we present a collection of 171 full-length single-cell RNA-seq datasets to explore the cellular landscape of circRNAs in human and mouse tissues. Through large-scale integrative analysis, we identify a total of 139,643 human and 214,747 mouse circRNAs in these scRNA-seq libraries. We validate the detected circRNAs with the integration of 11 bulk RNA-seq based resources, where 216,602 high-confidence circRNAs are uniquely detected in the single-cell cohort. We reveal the cell-type-specific expression pattern of circRNAs in brain samples, developing embryos, and breast tumors. We identify the uniquely expressed circRNAs in different cell types and validate their performance in tumor-infiltrating immune cell composition deconvolution. This study expands our knowledge of circRNA expression to the single-cell level and provides a useful resource for exploring circRNAs at this unprecedented resolution.
    DOI:  https://doi.org/10.1038/s41467-022-30963-8
  14. Nat Commun. 2022 Jun 07. 13(1): 3284
    Mafa-dependent GABAergic activity promotes mouse neonatal apneas.
    Laure Lecoin, Bowen Dempsey, Alexandra Garancher, Steeve Bourane, Pierre-Louis Ruffault, Marie-Pierre Morin-Surun, Nathalie Rocques, Martyn Goulding, Alain Eychène, Celio Pouponnot, Gilles Fortin, Jean Champagnat.
      While apneas are associated with multiple pathological and fatal conditions, the underlying molecular mechanisms remain elusive. We report that a mutated form of the transcription factor Mafa (Mafa4A) that prevents phosphorylation of the Mafa protein leads to an abnormally high incidence of breath holding apneas and death in newborn Mafa4A/4A mutant mice. This apneic breathing is phenocopied by restricting the mutation to central GABAergic inhibitory neurons and by activation of inhibitory Mafa neurons while reversed by inhibiting GABAergic transmission centrally. We find that Mafa activates the Gad2 promoter in vitro and that this activation is enhanced by the mutation that likely results in increased inhibitory drives onto target neurons. We also find that Mafa inhibitory neurons are absent from respiratory, sensory (primary and secondary) and pontine structures but are present in the vicinity of the hypoglossal motor nucleus including premotor neurons that innervate the geniohyoid muscle, to control upper airway patency. Altogether, our data reveal a role for Mafa phosphorylation in regulation of GABAergic drives and suggest a mechanism whereby reduced premotor drives to upper airway muscles may cause apneic breathing at birth.
    DOI:  https://doi.org/10.1038/s41467-022-30825-3
  15. Sci Immunol. 2022 Jun 03. 7(72): eabn2888
    The mammalian SKIV2L RNA exosome is essential for early B cell development.
    Kun Yang, Jie Han, Jennifer G Gill, Jason Y Park, Meghana N Sathe, Jyothsna Gattineni, Tracey Wright, Christian Wysocki, M Teresa de la Morena, Nan Yan.
      The SKIV2L RNA exosome is an evolutionarily conserved RNA degradation complex in the eukaryotes. Mutations in the SKIV2L gene are associated with a severe inherited disorder, trichohepatoenteric syndrome (THES), with multisystem involvement but unknown disease mechanism. Here, we reported a THES patient with SKIV2L mutations showing severe primary B cell immunodeficiency, hypogammaglobulinemia, and kappa-restricted plasma cell dyscrasia but normal T cell and NK cell function. To corroborate these findings, we made B cell-specific Skiv2l knockout mice (Skiv2lfl/flCd79a-Cre), which lacked both conventional B-2 and innate-like B-1 B cells in the periphery and secondary lymphoid organs. This was linked to a requirement of SKIV2L RNA exosome activity in the bone marrow during early B cell development at the pro-B cell to large pre-B cell transition. Mechanistically, Skiv2l-deficient pro-B cells exhibited cell cycle arrest and DNA damage. Furthermore, loss of Skiv2l led to substantial out-of-frame V(D)J rearrangement of immunoglobulin heavy chain and severely reduced surface expression of μH, both of which are crucial for pre-BCR signaling and proliferative burst during early B cell development. Together, our data demonstrated a crucial role for SKIV2L RNA exosome in early B cell development in both human and mice by ensuring proper V(D)J recombination and Igh expression, which serves as the molecular basis for immunodeficiency associated with THES.
    DOI:  https://doi.org/10.1126/sciimmunol.abn2888
  16. Nat Biotechnol. 2022 Jun 06.
    Variant to function mapping at single-cell resolution through network propagation.
    Fulong Yu, Liam D Cato, Chen Weng, L Alexander Liggett, Soyoung Jeon, Keren Xu, Charleston W K Chiang, Joseph L Wiemels, Jonathan S Weissman, Adam J de Smith, Vijay G Sankaran.
      Genome-wide association studies in combination with single-cell genomic atlases can provide insights into the mechanisms of disease-causal genetic variation. However, identification of disease-relevant or trait-relevant cell types, states and trajectories is often hampered by sparsity and noise, particularly in the analysis of single-cell epigenomic data. To overcome these challenges, we present SCAVENGE, a computational algorithm that uses network propagation to map causal variants to their relevant cellular context at single-cell resolution. We demonstrate how SCAVENGE can help identify key biological mechanisms underlying human genetic variation, applying the method to blood traits at distinct stages of human hematopoiesis, to monocyte subsets that increase the risk for severe Coronavirus Disease 2019 (COVID-19) and to intermediate lymphocyte developmental states that predispose to acute leukemia. Our approach not only provides a framework for enabling variant-to-function insights at single-cell resolution but also suggests a more general strategy for maximizing the inferences that can be made using single-cell genomic data.
    DOI:  https://doi.org/10.1038/s41587-022-01341-y
  17. Commun Biol. 2022 Jun 06. 5(1): 544
    Sirt6-mediated epigenetic modification of DNA accessibility is essential for Pou2f3-induced thymic tuft cell development.
    Qian Zhang, Jiayu Zhang, Tong Lei, Zhanfeng Liang, Xue Dong, Liguang Sun, Yong Zhao.
      Thymic epithelial cells (TECs) are essential for the production of self-tolerant T cells. The newly identified thymic tuft cells are regulated by Pou2f3 and represent important elements for host type 2 immunity. However, epigenetic involvement in thymic tuft cell development remains unclear. We performed single-cell ATAC-seq of medullary TEC (mTEC) and established single-cell chromatin accessibility profiling of mTECs. The results showed that mTEC III cells can be further divided into three groups (Late Aire 1, 2, and 3) and that thymic tuft cells may be derived from Late Aire 2 cells. Pou2f3 is expressed in both Late Aire 2 cells and thymic tuft cells, while Pou2f3-regulated genes are specifically expressed in thymic tuft cells with simultaneous opening of chromatin accessibility, indicating the involvement of epigenetic modification in this process. Using the epigenetic regulator Sirt6-defect mouse model, we found that Sirt6 deletion increased Late Aire 2 cells and decreased thymic tuft cells and Late Aire 3 cells without affecting Pou2f3 expression. However, Sirt6 deletion reduced the chromatin accessibility of Pou2f3-regulated genes in thymic tuft cells, which may be caused by Sirt6-mediated regulation of Hdac9 expression. These data indicate that epigenetic regulation is indispensable for Pou2f3-mediated thymic tuft cell development.
    DOI:  https://doi.org/10.1038/s42003-022-03484-9
  18. Nat Commun. 2022 Jun 08. 13(1): 3177
    Taf2 mediates DNA binding of Taf14.
    Brianna J Klein, Jordan T Feigerle, Jibo Zhang, Christopher C Ebmeier, Lixin Fan, Rohit K Singh, Wesley W Wang, Lauren R Schmitt, Thomas Lee, Kirk C Hansen, Wenshe R Liu, Yun-Xing Wang, Brian D Strahl, P Anthony Weil, Tatiana G Kutateladze.
      The assembly and function of the yeast general transcription factor TFIID complex requires specific contacts between its Taf14 and Taf2 subunits, however, the mechanism underlying these contacts remains unclear. Here, we determined the molecular and structural basis by which the YEATS and ET domains of Taf14 bind to the C-terminal tail of Taf2 and identified a unique DNA-binding activity of the linker region connecting the two domains. We show that in the absence of ligands the linker region of Taf14 is occluded by the surrounding domains, and therefore the DNA binding function of Taf14 is autoinhibited. Binding of Taf2 promotes a conformational rearrangement in Taf14, resulting in a release of the linker for the engagement with DNA and the nucleosome. Genetic in vivo data indicate that the association of Taf14 with both Taf2 and DNA is essential for transcriptional regulation. Our findings provide a basis for deciphering the role of individual TFIID subunits in mediating gene transcription.
    DOI:  https://doi.org/10.1038/s41467-022-30937-w
  19. Nat Commun. 2022 Jun 08. 13(1): 3180
    Control of CRK-RAC1 activity by the miR-1/206/133 miRNA family is essential for neuromuscular junction function.
    Ina Klockner, Christian Schutt, Theresa Gerhardt, Thomas Boettger, Thomas Braun.
      Formation and maintenance of neuromuscular junctions (NMJs) are essential for skeletal muscle function, allowing voluntary movements and maintenance of the muscle tone, thereby preventing atrophy. Generation of NMJs depends on the interaction of motor neurons with skeletal muscle fibers, which initiates a cascade of regulatory events that is essential for patterning of acetylcholine receptor (AChR) clusters at specific sites of the sarcolemma. Here, we show that muscle-specific miRNAs of the miR-1/206/133 family are crucial regulators of a signaling cascade comprising DOK7-CRK-RAC1, which is critical for stabilization and anchoring of postsynaptic AChRs during NMJ development and maintenance. We describe that posttranscriptional repression of CRK by miR-1/206/133 is essential for balanced activation of RAC1. Failure to adjust RAC1 activity severely compromises NMJ function, causing respiratory failure in neonates and neuromuscular symptoms in adult mice. We conclude that miR-1/206/133 serve a specific function for NMJs but are dispensable for skeletal muscle development.
    DOI:  https://doi.org/10.1038/s41467-022-30778-7
  20. Nat Commun. 2022 Jun 09. 13(1): 3202
    Norepinephrine potentiates and serotonin depresses visual cortical responses by transforming eligibility traces.
    Su Z Hong, Lukas Mesik, Cooper D Grossman, Jeremiah Y Cohen, Boram Lee, Hey-Kyoung Lee, Johannes W Hell, Alfredo Kirkwood.
      Reinforcement allows organisms to learn which stimuli predict subsequent biological relevance. Hebbian mechanisms of synaptic plasticity are insufficient to account for reinforced learning because neuromodulators signaling biological relevance are delayed with respect to the neural activity associated with the stimulus. A theoretical solution is the concept of eligibility traces (eTraces), silent synaptic processes elicited by activity which upon arrival of a neuromodulator are converted into a lasting change in synaptic strength. Previously we demonstrated in visual cortical slices the Hebbian induction of eTraces and their conversion into LTP and LTD by the retroactive action of norepinephrine and serotonin Here we show in vivo in mouse V1 that the induction of eTraces and their conversion to LTP/D by norepinephrine and serotonin respectively potentiates and depresses visual responses. We also show that the integrity of this process is crucial for ocular dominance plasticity, a canonical model of experience-dependent plasticity.
    DOI:  https://doi.org/10.1038/s41467-022-30827-1
  21. Nat Commun. 2022 Jun 07. 13(1): 3263
    JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation.
    Marta Vicioso-Mantis, Raquel Fueyo, Claudia Navarro, Sara Cruz-Molina, Wilfred F J van Ijcken, Elena Rebollo, Álvaro Rada-Iglesias, Marian A Martínez-Balbás.
      Enhancers are key regulatory elements that govern gene expression programs in response to developmental signals. However, how multiple enhancers arrange in the 3D-space to control the activation of a specific promoter remains unclear. To address this question, we exploited our previously characterized TGFβ-response model, the neural stem cells, focusing on a ~374 kb locus where enhancers abound. Our 4C-seq experiments reveal that the TGFβ pathway drives the assembly of an enhancer-cluster and precise gene activation. We discover that the TGFβ pathway coactivator JMJD3 is essential to maintain these structures. Using live-cell imaging techniques, we demonstrate that an intrinsically disordered region contained in JMJD3 is involved in the formation of phase-separated biomolecular condensates, which are found in the enhancer-cluster. Overall, in this work we uncover novel functions for the coactivator JMJD3, and we shed light on the relationships between the 3D-conformation of the chromatin and the TGFβ-driven response during mammalian neurogenesis.
    DOI:  https://doi.org/10.1038/s41467-022-30614-y
  22. Nat Commun. 2022 Jun 07. 13(1): 3257
    Structural basis for MTA1c-mediated DNA N6-adenine methylation.
    Jiyun Chen, Rong Hu, Ying Chen, Xiaofeng Lin, Wenwen Xiang, Hong Chen, Canglin Yao, Liang Liu.
      DNA N6-adenine methylation (6 mA) has recently been found to play a crucial role in epigenetic regulation in eukaryotes. MTA1c, a newly discovered 6 mA methyltransferase complex in ciliates, is composed of MTA1, MTA9, p1 and p2 subunits and specifically methylates ApT dinucleotides, yet its mechanism of action remains unknown. Here, we report the structures of Tetrahymena thermophila MTA1 (TthMTA1), Paramecium tetraurelia MTA9 (PteMTA9)-TthMTA1 binary complex, as well as the structures of TthMTA1-p1-p2 and TthMTA1-p2 complexes in apo, S-adenosyl methionine-bound and S-adenosyl homocysteine-bound states. We show that MTA1 is the catalytically active subunit, p1 and p2 are involved in the formation of substrate DNA-binding channel, and MTA9 plays a structural role in the stabilization of substrate binding. We identify that MTA1 is a cofactor-dependent catalytically active subunit, which exhibits stable SAM-binding activity only after assembly with p2. Our structures and corresponding functional studies provide a more detailed mechanistic understanding of 6 mA methylation.
    DOI:  https://doi.org/10.1038/s41467-022-31060-6
  23. Nat Commun. 2022 Jun 08. 13(1): 3176
    Leukocyte cell-derived chemotaxin 2 is an antiviral regulator acting through the proto-oncogene MET.
    Takayoshi Shirasaki, Satoshi Yamagoe, Tetsuro Shimakami, Kazuhisa Murai, Ryu Imamura, Kiyo-Aki Ishii, Hiroaki Takayama, Yukako Matsumoto, Natsumi Tajima-Shirasaki, Naoto Nagata, Ryogo Shimizu, Souma Yamanaka, Atsushi Abe, Hitoshi Omura, Kazunori Kawaguchi, Hikari Okada, Taro Yamashita, Tomoki Yoshikawa, Kazuhiro Takimoto, Motoko Taharaguchi, Shogo Takatsuka, Yoshitsugu Miyazaki, Toshikatsu Tamai, Yamato Tanabe, Makoto Kurachi, Yasuhiko Yamamoto, Shuichi Kaneko, Kunio Matsumoto, Toshinari Takamura, Masao Honda.
      Retinoic acid-inducible gene (RIG)-I is an essential innate immune sensor that recognises pathogen RNAs and induces interferon (IFN) production. However, little is known about how host proteins regulate RIG-I activation. Here, we show that leukocyte cell-derived chemotaxin 2 (LECT2), a hepatokine and ligand of the MET receptor tyrosine kinase is an antiviral regulator that promotes the RIG-I-mediated innate immune response. Upon binding to MET, LECT2 induces the recruitment of the phosphatase PTP4A1 to MET and facilitates the dissociation and dephosphorylation of phosphorylated SHP2 from MET, thereby protecting RIG-I from SHP2/c-Cbl-mediated degradation. In vivo, LECT2 overexpression enhances RIG-I-dependent IFN production and inhibits lymphocytic choriomeningitis virus (LCMV) replication in the liver, whereas these changes are reversed in LECT2 knockout mice. Forced suppression of MET abolishes IFN production and antiviral activity in vitro and in vivo. Interestingly, hepatocyte growth factor (HGF), an original MET ligand, inhibits LECT2-mediated anti-viral signalling; conversely, LECT2-MET signalling competes with HGF-MET signalling. Our findings reveal previously unrecognized crosstalk between MET-mediated proliferation and innate immunity and suggest that targeting LECT2 may have therapeutic value in infectious diseases and cancer.
    DOI:  https://doi.org/10.1038/s41467-022-30879-3
  24. Nat Commun. 2022 Jun 07. 13(1): 3279
    Re-programming mouse liver-resident invariant natural killer T cells for suppressing hepatic and diabetogenic autoimmunity.
    Channakeshava Sokke Umeshappa, Patricia Solé, Jun Yamanouchi, Saswat Mohapatra, Bas G J Surewaard, Josep Garnica, Santiswarup Singha, Debajyoti Mondal, Elena Cortés-Vicente, Charlotte D'Mello, Andrew Mason, Paul Kubes, Pau Serra, Yang Yang, Pere Santamaria.
      Invariant NKT (iNKT) cells comprise a heterogeneous group of non-circulating, tissue-resident T lymphocytes that recognize glycolipids, including alpha-galactosylceramide (αGalCer), in the context of CD1d, but whether peripheral iNKT cell subsets are terminally differentiated remains unclear. Here we show that mouse and human liver-resident αGalCer/CD1d-binding iNKTs largely correspond to a novel Zbtb16+Tbx21+Gata3+MaflowRorc- subset that exhibits profound transcriptional, phenotypic and functional plasticity. Repetitive in vivo encounters of these liver iNKT (LiNKT) cells with intravenously delivered αGalCer/CD1d-coated nanoparticles (NP) trigger their differentiation into immunoregulatory, IL-10+IL-21-producing Zbtb16highMafhighTbx21+Gata3+Rorc- cells, termed LiNKTR1, expressing a T regulatory type 1 (TR1)-like transcriptional signature. This response is LiNKT-specific, since neither lung nor splenic tissue-resident iNKT cells from αGalCer/CD1d-NP-treated mice produce IL-10 or IL-21. Additionally, these LiNKTR1 cells suppress autoantigen presentation, and recognize CD1d expressed on conventional B cells to induce IL-10+IL-35-producing regulatory B (Breg) cells, leading to the suppression of liver and pancreas autoimmunity. Our results thus suggest that LiNKT cells are plastic for further functional diversification, with such plasticity potentially targetable for suppressing tissue-specific inflammatory phenomena.
    DOI:  https://doi.org/10.1038/s41467-022-30759-w
  25. Commun Biol. 2022 Jun 06. 5(1): 549
    Comprehensive identification of SWI/SNF complex subunits underpins deep eukaryotic ancestry and reveals new plant components.
    Jorge Hernández-García, Borja Diego-Martin, Peggy Hsuanyu Kuo, Yasaman Jami-Alahmadi, Ajay A Vashisht, James Wohlschlegel, Steven E Jacobsen, Miguel A Blázquez, Javier Gallego-Bartolomé.
      Over millions of years, eukaryotes evolved from unicellular to multicellular organisms with increasingly complex genomes and sophisticated gene expression networks. Consequently, chromatin regulators evolved to support this increased complexity. The ATP-dependent chromatin remodelers of the SWI/SNF family are multiprotein complexes that modulate nucleosome positioning and appear under different configurations, which perform distinct functions. While the composition, architecture, and activity of these subclasses are well understood in a limited number of fungal and animal model organisms, the lack of comprehensive information in other eukaryotic organisms precludes the identification of a reliable evolutionary model of SWI/SNF complexes. Here, we performed a systematic analysis using 36 species from animal, fungal, and plant lineages to assess the conservation of known SWI/SNF subunits across eukaryotes. We identified evolutionary relationships that allowed us to propose the composition of a hypothetical ancestral SWI/SNF complex in the last eukaryotic common ancestor. This last common ancestor appears to have undergone several rounds of lineage-specific subunit gains and losses, shaping the current conformation of the known subclasses in animals and fungi. In addition, our results unravel a plant SWI/SNF complex, reminiscent of the animal BAF subclass, which incorporates a set of plant-specific subunits of still unknown function.
    DOI:  https://doi.org/10.1038/s42003-022-03490-x
  26. Nat Commun. 2022 Jun 03. 13(1): 3121
    Ex vivo-expanded human CD19+TIM-1+ regulatory B cells suppress immune responses in vivo and are dependent upon the TIM-1/STAT3 axis.
    S Shankar, J Stolp, S C Juvet, J Beckett, P S Macklin, F Issa, J Hester, K J Wood.
      Regulatory B cells (Breg) are a heterogenous population with immune-modulating functions. The rarity of human IL-10+ Breg makes translational studies difficult. Here we report ex vivo expansion of human B cells with in vivo regulatory function (expBreg). CD154-stimulation of human CD19+ B cells drives >900-fold expansion of IL-10+ B cells that is maintained in culture for 14 days. Whilst expBreg-mediated suppressive function is partially dependent on IL-10 expression, CRISPR-mediated gene deletions demonstrate predominant roles for TIM-1 and CD154. TIM-1 regulates STAT3 signalling and modulates downstream suppressive function. In a clinically relevant humanised mouse model of skin transplantation, expBreg prolongs human allograft survival. Meanwhile, CD19+CD73-CD25+CD71+TIM-1+CD154+ Breg cells are enriched in the peripheral blood of human donors with cutaneous squamous cell carcinoma (SCC). TIM-1+ and pSTAT3+ B cells are also identified in B cell clusters within histological sections of human cutaneous SCC tumours. Our findings thus provide insights on Breg homoeostasis and present possible targets for Breg-related therapies.
    DOI:  https://doi.org/10.1038/s41467-022-30613-z
  27. Nature. 2022 Jun 08.
    A preoptic neuronal population controls fever and appetite during sickness.
    Jessica A Osterhout, Vikrant Kapoor, Stephen W Eichhorn, Eric Vaughn, Jeffrey D Moore, Ding Liu, Dean Lee, Laura A DeNardo, Liqun Luo, Xiaowei Zhuang, Catherine Dulac.
      During infection, animals exhibit adaptive changes in physiology and behaviour aimed at increasing survival. Although many causes of infection exist, they trigger similar stereotyped symptoms such as fever, warmth-seeking, loss of appetite and fatigue1,2. Yet exactly how the nervous system alters body temperature and triggers sickness behaviours to coordinate responses to infection remains unknown. Here we identify a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness induced by lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid. These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite. Single-nucleus RNA-sequencing and multiplexed error-robust fluorescence in situ hybridization uncovered the identity and distribution of LPS-activated VMPO (VMPOLPS) neurons and non-neuronal cells. Gene expression and electrophysiological measurements implicate a paracrine mechanism in which the release of immune signals by non-neuronal cells during infection activates nearby VMPOLPS neurons. Finally, we show that VMPOLPS neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite. Together, these results uncover VMPOLPS neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection.
    DOI:  https://doi.org/10.1038/s41586-022-04793-z
  28. Nat Commun. 2022 Jun 09. 13(1): 3230
    Efferocytosis requires periphagosomal Ca2+-signaling and TRPM7-mediated electrical activity.
    Michael S Schappe, Marta E Stremska, Gregory W Busey, Taylor K Downs, Philip V Seegren, Suresh K Mendu, Zachary Flegal, Catherine A Doyle, Eric J Stipes, Bimal N Desai.
      Efficient clearance of apoptotic cells by phagocytosis, also known as efferocytosis, is fundamental to developmental biology, organ physiology, and immunology. Macrophages use multiple mechanisms to detect and engulf apoptotic cells, but the signaling pathways that regulate the digestion of the apoptotic cell cargo, such as the dynamic Ca2+ signals, are poorly understood. Using an siRNA screen, we identify TRPM7 as a Ca2+-conducting ion channel essential for phagosome maturation during efferocytosis. Trpm7-targeted macrophages fail to fully acidify or digest their phagosomal cargo in the absence of TRPM7. Through perforated patch electrophysiology, we demonstrate that TRPM7 mediates a pH-activated cationic current necessary to sustain phagosomal acidification. Using mice expressing a genetically-encoded Ca2+ sensor, we observe that phagosome maturation requires peri-phagosomal Ca2+-signals dependent on TRPM7. Overall, we reveal TRPM7 as a central regulator of phagosome maturation during macrophage efferocytosis.
    DOI:  https://doi.org/10.1038/s41467-022-30959-4
  29. Nat Commun. 2022 Jun 07. 13(1): 3245
    Immune monitoring and treatment in immune-mediated inflammatory diseases.
    Femke van Wijk, Marjolein de Bruin, Helen Leavis, Stefan Nierkens.
      
    DOI:  https://doi.org/10.1038/s41467-022-30891-7
  30. Nature. 2022 Jun 08.
    Cohesin-mediated loop anchors confine the locations of human replication origins.
    Daniel J Emerson, Peiyao A Zhao, Ashley L Cook, R Jordan Barnett, Kyle N Klein, Dalila Saulebekova, Chunmin Ge, Linda Zhou, Zoltan Simandi, Miriam K Minsk, Katelyn R Titus, Weitao Wang, Wanfeng Gong, Di Zhang, Liyan Yang, Sergey V Venev, Johan H Gibcus, Hongbo Yang, Takayo Sasaki, Masato T Kanemaki, Feng Yue, Job Dekker, Chun-Long Chen, David M Gilbert, Jennifer E Phillips-Cremins.
      DNA replication occurs through an intricately regulated series of molecular events and is fundamental for genome stability1,2. At present, it is unknown how the locations of replication origins are determined in the human genome. Here we dissect the role of topologically associating domains (TADs)3-6, subTADs7 and loops8 in the positioning of replication initiation zones (IZs). We stratify TADs and subTADs by the presence of corner-dots indicative of loops and the orientation of CTCF motifs. We find that high-efficiency, early replicating IZs localize to boundaries between adjacent corner-dot TADs anchored by high-density arrays of divergently and convergently oriented CTCF motifs. By contrast, low-efficiency IZs localize to weaker dotless boundaries. Following ablation of cohesin-mediated loop extrusion during G1, high-efficiency IZs become diffuse and delocalized at boundaries with complex CTCF motif orientations. Moreover, G1 knockdown of the cohesin unloading factor WAPL results in gained long-range loops and narrowed localization of IZs at the same boundaries. Finally, targeted deletion or insertion of specific boundaries causes local replication timing shifts consistent with IZ loss or gain, respectively. Our data support a model in which cohesin-mediated loop extrusion and stalling at a subset of genetically encoded TAD and subTAD boundaries is an essential determinant of the locations of replication origins in human S phase.
    DOI:  https://doi.org/10.1038/s41586-022-04803-0
  31. Nat Commun. 2022 Jun 03. 13(1): 3111
    High resolution microfluidic assay and probabilistic modeling reveal cooperation between T cells in tumor killing.
    Gustave Ronteix, Shreyansh Jain, Christelle Angely, Marine Cazaux, Roxana Khazen, Philippe Bousso, Charles N Baroud.
      Cytotoxic T cells are important components of natural anti-tumor immunity and are harnessed in tumor immunotherapies. Immune responses to tumors and immune therapy outcomes largely vary among individuals, but very few studies examine the contribution of intrinsic behavior of the T cells to this heterogeneity. Here we show the development of a microfluidic-based in vitro method to track the outcome of antigen-specific T cell activity on many individual cancer spheroids simultaneously at high spatiotemporal resolution, which we call Multiscale Immuno-Oncology on-Chip System (MIOCS). By combining parallel measurements of T cell behaviors and tumor fates with probabilistic modeling, we establish that the first recruited T cells initiate a positive feedback loop to accelerate further recruitment to the spheroid. We also provide evidence that cooperation between T cells on the spheroid during the killing phase facilitates tumor destruction. Thus, we propose that both T cell accumulation and killing function rely on collective behaviors rather than simply reflecting the sum of individual T cell activities, and the possibility to track many replicates of immune cell-tumor interactions with the level of detail our system provides may contribute to our understanding of immune response heterogeneity.
    DOI:  https://doi.org/10.1038/s41467-022-30575-2
  32. Nature. 2022 Jun 03.
    A surprise in the eye: long-lived T cells patrol the cornea.
    Smriti Mallapaty.
      
    Keywords:  Diseases; Infection; Microscopy
    DOI:  https://doi.org/10.1038/d41586-022-01578-2
  33. Sci Immunol. 2022 Jun 03. 7(72): eabn2738
    RNA exosome drives early B cell development via noncoding RNA processing mechanisms.
    Brice Laffleur, Carolina R Batista, Wanwei Zhang, Junghyun Lim, Biao Yang, Delphine Rossille, Lijing Wu, Jerson Estrella, Gerson Rothschild, Evangelos Pefanis, Uttiya Basu.
      B cell development is linked to successful V(D)J recombination, allowing B cell receptor expression and ultimately antibody secretion for adaptive immunity. Germline noncoding RNAs (ncRNAs) are produced at immunoglobulin (Ig) loci during V(D)J recombination, but their function and posttranscriptional regulation are incompletely understood. Patients with trichohepatoenteric syndrome, characterized by RNA exosome pathway component mutations, exhibit lymphopenia, thus demonstrating the importance of ncRNA surveillance in B cell development in humans. To understand the role of RNA exosome in early B cell development in greater detail, we generated mouse models harboring a B cell-specific cre allele (Mb1cre), coupled to conditional inversion-deletion alleles of one RNA exosome core component (Exosc3) or RNase catalytic subunits (Exosc10 or Dis3). We noticed increased expression of RNA exosome subunits during V(D)J recombination, whereas a B cell developmental blockade at the pro-B cell stage was observed in the different knockout mice, overlapping with a lack of productive rearrangements of VDJ genes at the Ig heavy chain (Igh). This unsuccessful recombination prevented differentiation into pre-B cells, with accumulation of ncRNAs and up-regulation of the p53 pathway. Introduction of a prearranged Igh VDJ allele partly rescued the pre-B cell population in Dis3-deficient cells, although V-J recombination defects were observed at Ig light chain kappa (Igκ), preventing subsequent B cell development. These observations demonstrated that the RNA exosome complex is important for Igh and Igκ recombination and establish the relevance of RNA processing for optimal diversification at these loci during B cell development.
    DOI:  https://doi.org/10.1126/sciimmunol.abn2738
  34. Nat Commun. 2022 Jun 07. 13(1): 3272
    Molecular basis of mEAK7-mediated human V-ATPase regulation.
    Rong Wang, Yu Qin, Xiao-Song Xie, Xiaochun Li.
      The activity of V-ATPase is well-known to be regulated by reversible dissociation of its V1 and Vo domains in response to growth factor stimulation, nutrient sensing, and cellular differentiation. The molecular basis of its regulation by an endogenous modulator without affecting V-ATPase assembly remains unclear. Here, we discover that a lysosome-anchored protein termed (mammalian Enhancer-of-Akt-1-7 (mEAK7)) binds to intact V-ATPase. We determine cryo-EM structure of human mEAK7 in complex with human V-ATPase in native lipid-containing nanodiscs. The structure reveals that the TLDc domain of mEAK7 engages with subunits A, B, and E, while its C-terminal domain binds to subunit D, presumably blocking V1-Vo torque transmission. Our functional studies suggest that mEAK7, which may act as a V-ATPase inhibitor, does not affect the activity of V-ATPase in vitro. However, overexpression of mEAK7 in HCT116 cells that stably express subunit a4 of V-ATPase represses the phosphorylation of ribosomal protein S6. Thus, this finding suggests that mEAK7 potentially links mTOR signaling with V-ATPase activity.
    DOI:  https://doi.org/10.1038/s41467-022-30899-z
  35. Cell Res. 2022 Jun 03.
    Nuclear RIPK1 promotes chromatin remodeling to mediate inflammatory response.
    Wanjin Li, Bing Shan, Chengyu Zou, Huibing Wang, Meng-Meng Zhang, Hong Zhu, Masanori Gomi Naito, Daichao Xu, Vica Jean Manuel, Lauren Mifflin, Zhaodong Hou, John Ravits, Junying Yuan.
      RIPK1 is a master regulator of multiple cell death pathways, including apoptosis and necroptosis, and inflammation. Importantly, activation of RIPK1 has also been shown to promote the transcriptional induction of proinflammatory cytokines in cells undergoing necroptosis, in animal models of amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD), and in human ALS and AD. Rare human genetic carriers of non-cleavable RIPK1 variants (D324V and D324H) exhibit distinct symptoms of recurrent fevers and increased transcription of proinflammatory cytokines. Multiple RIPK1 inhibitors have been advanced into human clinical trials as new therapeutics for human inflammatory and neurodegenerative diseases, such as ALS and AD. However, it is unclear whether and how RIPK1 kinase activity directly mediates inflammation independent of cell death as the nuclear function of RIPK1 has not yet been explored. Here we show that nuclear RIPK1 is physically associated with the BAF complex. Upon RIPK1 activation, the RIPK1/BAF complex is recruited by specific transcription factors to active enhancers and promoters marked by H3K4me1 and H3K27ac. Activated nuclear RIPK1 mediates the phosphorylation of SMARCC2, a key component of the BAF complex, to promote chromatin remodeling and the transcription of specific proinflammatory genes. Increased nuclear RIPK1 activation and RIPK1/BAF-mediated chromatin-remodeling activity were found in cells expressing non-cleavable RIPK1, and increased enrichment of activated RIPK1 on active enhancers and promoters was found in an animal model and human pathological samples of ALS. Our results suggest that RIPK1 kinase serves as a transcriptional coregulator in nucleus that can transmit extracellular stimuli to the BAF complex to modulate chromatin accessibility and directly regulate the transcription of specific genes involved in mediating inflammatory responses.
    DOI:  https://doi.org/10.1038/s41422-022-00673-3
  36. Nat Commun. 2022 Jun 08. 13(1): 3294
    Hippocampal representations switch from errors to predictions during acquisition of predictive associations.
    Fraser Aitken, Peter Kok.
      We constantly exploit the statistical regularities in our environment to help guide our perception. The hippocampus has been suggested to play a pivotal role in both learning environmental statistics, as well as exploiting them to generate perceptual predictions. However, it is unclear how the hippocampus balances encoding new predictive associations with the retrieval of existing ones. Here, we present the results of two high resolution human fMRI studies (N = 24 for both experiments) directly investigating this. Participants were exposed to auditory cues that predicted the identity of an upcoming visual shape (with 75% validity). Using multivoxel decoding analysis, we find that the hippocampus initially preferentially represents unexpected shapes (i.e., those that violate the cue regularities), but later switches to representing the cue-predicted shape regardless of which was actually presented. These findings demonstrate that the hippocampus is involved both acquiring and exploiting predictive associations, and is dominated by either errors or predictions depending on whether learning is ongoing or complete.
    DOI:  https://doi.org/10.1038/s41467-022-31040-w
  37. Nat Commun. 2022 Jun 09. 13(1): 3336
    Profiling Fusobacterium infection at high taxonomic resolution reveals lineage-specific correlations in colorectal cancer.
    Dexi Bi, Yin Zhu, Yaohui Gao, Hao Li, Xingchen Zhu, Rong Wei, Ruting Xie, Chunmiao Cai, Qing Wei, Huanlong Qin.
      The bacterial genus Fusobacterium promotes colorectal cancer (CRC) development, but an understanding of its precise composition at the species level in the human gut and the relevant association with CRC is lacking. Herein, we devise a Fusobacterium rpoB amplicon sequencing (FrpoB-seq) method that enables the differentiation of Fusobacterium species and certain subspecies in the microbiota. By applying this method to clinical tissue and faecal samples from CRC patients, we detect 62 Fusobacterium species, including 45 that were previously undescribed. We additionally reveal that Fusobacterium species may display different lineage-dependent functions in CRC. Specifically, a lineage (designated L1) including F. nucleatum, F. hwasookii, F. periodonticum and their relatives (rather than any particular species alone) is overabundant in tumour samples and faeces from CRC patients, whereas a non-enriched lineage (designated L5) represented by F. varium and F. ulcerans in tumours has a positive association with lymphovascular invasion.
    DOI:  https://doi.org/10.1038/s41467-022-30957-6
  38. FASEB J. 2022 Jul;36(7): e22383
    Normalization of maternal adiponectin in obese pregnant mice prevents programming of impaired glucose metabolism in adult offspring.
    Jerad Dumolt, Theresa L Powell, Thomas Jansson, Fredrick J Rosario.
      Infants born to obese mothers have a greater risk for childhood obesity and insulin resistance. However, the underlying biological mechanism remains elusive, which constitutes a significant roadblock for developing specific prevention strategies. Maternal adiponectin levels are lower in obese pregnant women, which is linked with increased placental nutrient transport and fetal overgrowth. We have previously reported that adiponectin supplementation to obese dams during the last four days of pregnancy prevented the development of obesity, glucose intolerance, muscle insulin resistance, and fatty liver in three months old offspring. In the present study, we tested the hypothesis that 6-9-month-old offspring of obese dams show glucose intolerance associated with muscle insulin resistance and mitochondrial dysfunction and that normalization of maternal adiponectin in obese pregnant mice prevents the development of this phenotype in the offspring. Male and female offspring of obese mice exhibited in vivo glucose intolerance and insulin resistance at 6 and 9 months of age. In gastrocnemius muscles ex vivo, male and female offspring of obese dams showed reduced phosphorylation of insulin receptor substrate 1Tyr-608 , AktThr-308 , and decreased Glut4 plasma membrane translocation upon insulin stimulation. These metabolic abnormalities in offspring born to obese mice were largely prevented by normalization of maternal adiponectin levels in late pregnancy. We provide evidence that low circulating maternal adiponectin is a critical mechanistic link between maternal obesity and the development of metabolic disease in offspring. Strategies aimed at improving maternal adiponectin levels may prevent long-term metabolic dysfunction in offspring of obese mothers.
    Keywords:  fetal programming; glucose intolerance; insulin resistance; metabolic diseases
    DOI:  https://doi.org/10.1096/fj.202200326R
  39. Nat Commun. 2022 Jun 07. 13(1): 3145
    Dynamic nucleosome landscape elicits a noncanonical GATA2 pioneer model.
    Tianbao Li, Qi Liu, Zhong Chen, Kun Fang, Furong Huang, Xueqi Fu, Qianben Wang, Victor X Jin.
      Knowledge gaps remain on how nucleosome organization and dynamic reorganization are governed by specific pioneer factors in a genome-wide manner. In this study, we generate over three billons of multi-omics sequencing data to exploit dynamic nucleosome landscape governed by pioneer factors (PFs), FOXA1 and GATA2. We quantitatively define nine functional nucleosome states each with specific characteristic nucleosome footprints in LNCaP prostate cancer cells. Interestingly, we observe dynamic switches among nucleosome states upon androgen stimulation, accompanied by distinct differential (gained or lost) binding of FOXA1, GATA2, H1 as well as many other coregulators. Intriguingly, we reveal a noncanonical pioneer model of GATA2 that it initially functions as a PF binding at the edge of a nucleosome in an inaccessible crowding array. Upon androgen stimulation, GATA2 re-configures an inaccessible to accessible nucleosome state and subsequently acts as a master transcription factor either directly or recruits signaling specific transcription factors to enhance WNT signaling in an androgen receptor (AR)-independent manner. Our data elicit a pioneer and master dual role of GATA2 in mediating nucleosome dynamics and enhancing downstream signaling pathways. Our work offers structural and mechanistic insight into the dynamics of pioneer factors governing nucleosome reorganization.
    DOI:  https://doi.org/10.1038/s41467-022-30960-x
  40. Nat Commun. 2022 Jun 09. 13(1): 3218
    Large-scale multi-omics analysis suggests specific roles for intragenic cohesin in transcriptional regulation.
    Jiankang Wang, Masashige Bando, Katsuhiko Shirahige, Ryuichiro Nakato.
      Cohesin, an essential protein complex for chromosome segregation, regulates transcription through a variety of mechanisms. It is not a trivial task to assign diverse cohesin functions. Moreover, the context-specific roles of cohesin-mediated interactions, especially on intragenic regions, have not been thoroughly investigated. Here we perform a comprehensive characterization of cohesin binding sites in several human cell types. We integrate epigenomic, transcriptomic and chromatin interaction data to explore the context-specific functions of intragenic cohesin related to gene activation. We identify a specific subset of cohesin binding sites, decreased intragenic cohesin sites (DICs), which are negatively correlated with transcriptional regulation. A subgroup of DICs is enriched with enhancer markers and RNA polymerase II, while the others are more correlated to chromatin architecture. DICs are observed in various cell types, including cells from patients with cohesinopathy. We also implement machine learning to our data and identified genomic features for isolating DICs from all cohesin sites. These results suggest a previously unidentified function of cohesin on intragenic regions for transcriptional regulation.
    DOI:  https://doi.org/10.1038/s41467-022-30792-9
  41. Sci Adv. 2022 Jun 10. 8(23): eabj2820
    Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL.
    Zhiliang Bai, Steven Woodhouse, Ziran Zhao, Rahul Arya, Kiya Govek, Dongjoo Kim, Stefan Lundh, Alev Baysoy, Hongxing Sun, Yanxiang Deng, Yang Xiao, David M Barrett, Regina M Myers, Stephan A Grupp, Carl H June, Rong Fan, Pablo G Camara, J Joseph Melenhorst.
      A notable number of acute lymphoblastic leukemia (ALL) patients develop CD19-positive relapse within 1 year after receiving chimeric antigen receptor (CAR) T cell therapy. It remains unclear if the long-term response is associated with the characteristics of CAR T cells in infusion products, hindering the identification of biomarkers to predict therapeutic outcomes. Here, we present 101,326 single-cell transcriptomes and surface protein landscape from the infusion products of 12 ALL patients. We observed substantial heterogeneity in the antigen-specific activation states, among which a deficiency of T helper 2 function was associated with CD19-positive relapse compared with durable responders (remission, >54 months). Proteomic data revealed that the frequency of early memory T cells, rather than activation or coinhibitory signatures, could distinguish the relapse. These findings were corroborated by independent functional profiling of 49 patients, and an integrative model was developed to predict the response. Our data unveil the molecular mechanisms that may inform strategies to boost specific T cell function to maintain long-term remission.
    DOI:  https://doi.org/10.1126/sciadv.abj2820
  42. Nat Genet. 2022 Jun 06.
    Combining SNP-to-gene linking strategies to identify disease genes and assess disease omnigenicity.
    Steven Gazal, Omer Weissbrod, Farhad Hormozdiari, Kushal K Dey, Joseph Nasser, Karthik A Jagadeesh, Daniel J Weiner, Huwenbo Shi, Charles P Fulco, Luke J O'Connor, Bogdan Pasaniuc, Jesse M Engreitz, Alkes L Price.
      Disease-associated single-nucleotide polymorphisms (SNPs) generally do not implicate target genes, as most disease SNPs are regulatory. Many SNP-to-gene (S2G) linking strategies have been developed to link regulatory SNPs to the genes that they regulate in cis. Here, we developed a heritability-based framework for evaluating and combining different S2G strategies to optimize their informativeness for common disease risk. Our optimal combined S2G strategy (cS2G) included seven constituent S2G strategies and achieved a precision of 0.75 and a recall of 0.33, more than doubling the recall of any individual strategy. We applied cS2G to fine-mapping results for 49 UK Biobank diseases/traits to predict 5,095 causal SNP-gene-disease triplets (with S2G-derived functional interpretation) with high confidence. We further applied cS2G to provide an empirical assessment of disease omnigenicity; we determined that the top 1% of genes explained roughly half of the SNP heritability linked to all genes and that gene-level architectures vary with variant allele frequency.
    DOI:  https://doi.org/10.1038/s41588-022-01087-y
  43. Nat Commun. 2022 Jun 07. 13(1): 3271
    Serotonin and dopamine modulate aging in response to food odor and availability.
    Hillary A Miller, Shijiao Huang, Elizabeth S Dean, Megan L Schaller, Angela M Tuckowski, Allyson S Munneke, Safa Beydoun, Scott D Pletcher, Scott F Leiser.
      An organism's ability to perceive and respond to changes in its environment is crucial for its health and survival. Here we reveal how the most well-studied longevity intervention, dietary restriction, acts in-part through a cell non-autonomous signaling pathway that is inhibited by the presence of attractive smells. Using an intestinal reporter for a key gene induced by dietary restriction but suppressed by attractive smells, we identify three compounds that block food odor effects in C. elegans, thereby increasing longevity as dietary restriction mimetics. These compounds clearly implicate serotonin and dopamine in limiting lifespan in response to food odor. We further identify a chemosensory neuron that likely perceives food odor, an enteric neuron that signals through the serotonin receptor 5-HT1A/SER-4, and a dopaminergic neuron that signals through the dopamine receptor DRD2/DOP-3. Aspects of this pathway are conserved in D. melanogaster. Thus, blocking food odor signaling through antagonism of serotonin or dopamine receptors is a plausible approach to mimic the benefits of dietary restriction.
    DOI:  https://doi.org/10.1038/s41467-022-30869-5
  44. Cell Stem Cell. 2022 Jun 02. pii: S1934-5909(22)00161-8. [Epub ahead of print]29(6): 973-989.e10
    The spatiotemporal program of zonal liver regeneration following acute injury.
    Shani Ben-Moshe, Tamar Veg, Rita Manco, Stav Dan, Delfina Papinutti, Aviezer Lifshitz, Aleksandra A Kolodziejczyk, Keren Bahar Halpern, Eran Elinav, Shalev Itzkovitz.
      The liver carries a remarkable ability to regenerate rapidly after acute zonal damage. Single-cell approaches are necessary to study this process, given the spatial heterogeneity of liver cell types. Here, we use spatially resolved single-cell RNA sequencing (scRNA-seq) to study the dynamics of mouse liver regeneration after acute acetaminophen (APAP) intoxication. We find that hepatocytes proliferate throughout the liver lobule, creating the mitotic pressure required to repopulate the necrotic pericentral zone rapidly. A subset of hepatocytes located at the regenerating front transiently upregulate fetal-specific genes, including Afp and Cdh17, as they reprogram to a pericentral state. Zonated endothelial, hepatic stellate cell (HSC), and macrophage populations are differentially involved in immune recruitment, proliferation, and matrix remodeling. We observe massive transient infiltration of myeloid cells, yet stability of lymphoid cell abundance, in accordance with a global decline in antigen presentation. Our study provides a resource for understanding the coordinated programs of zonal liver regeneration.
    Keywords:  DILI; acetaminophen; acute liver failure; damage-induced liver injury; hepatocytes; liver regeneration; liver zonation; single-cell transcriptomics; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.stem.2022.04.008
  45. Sci Immunol. 2022 Jun 10. 7(72): eabn5917
    NuRD complex recruitment to Thpok mediates CD4+ T cell lineage differentiation.
    Yayi Gao, Monica Zamisch, Melanie Vacchio, Laura Chopp, Thomas Ciucci, Elliott L Paine, Gaelyn C Lyons, Jia Nie, Qi Xiao, Ekaterina Zvezdova, Paul E Love, Charles R Vinson, Lisa M Jenkins, Rémy Bosselut.
      Although BTB-zinc finger (BTB-ZF) transcription factors control the differentiation of multiple hematopoietic and immune lineages, how they function is poorly understood. The BTB-ZF factor Thpok controls intrathymic CD4+ T cell development and the expression of most CD4+ and CD8+ lineage genes. Here, we identify the nucleosome remodeling and deacetylase (NuRD) complex as a critical Thpok cofactor. Using mass spectrometry and coimmunoprecipitation in primary T cells, we show that Thpok binds NuRD components independently of DNA association. We locate three amino acid residues within the Thpok BTB domain that are required for both NuRD binding and Thpok functions. Conversely, a chimeric protein merging the NuRD component Mta2 to a BTB-less version of Thpok supports CD4+ T cell development, indicating that NuRD recruitment recapitulates the functions of the Thpok BTB domain. We found that NuRD mediates Thpok repression of CD8+ lineage genes, including the transcription factor Runx3, but is dispensable for Cd4 expression. We show that these functions cannot be performed by the BTB domain of the Thpok-related factor Bcl6, which fails to bind NuRD. Thus, cofactor binding critically contributes to the functional specificity of BTB-ZF factors, which control the differentiation of most hematopoietic subsets.
    DOI:  https://doi.org/10.1126/sciimmunol.abn5917
  46. Nat Cell Biol. 2022 Jun 09.
    Lysosome lipid signalling from the periphery to neurons regulates longevity.
    Marzia Savini, Andrew Folick, Yi-Tang Lee, Feng Jin, André Cuevas, Matthew C Tillman, Jonathon D Duffy, Qian Zhao, Isaiah A Neve, Pei-Wen Hu, Yong Yu, Qinghao Zhang, Youqiong Ye, William B Mair, Jin Wang, Leng Han, Eric A Ortlund, Meng C Wang.
      Lysosomes are key cellular organelles that metabolize extra- and intracellular substrates. Alterations in lysosomal metabolism are implicated in ageing-associated metabolic and neurodegenerative diseases. However, how lysosomal metabolism actively coordinates the metabolic and nervous systems to regulate ageing remains unclear. Here we report a fat-to-neuron lipid signalling pathway induced by lysosomal metabolism and its longevity-promoting role in Caenorhabditis elegans. We discovered that induced lysosomal lipolysis in peripheral fat storage tissue upregulates the neuropeptide signalling pathway in the nervous system to promote longevity. This cell-non-autonomous regulation is mediated by a specific polyunsaturated fatty acid, dihomo-γ-linolenic acid, and LBP-3 lipid chaperone protein transported from the fat storage tissue to neurons. LBP-3 binds to dihomo-γ-linolenic acid, and acts through NHR-49 nuclear receptor and NLP-11 neuropeptide in neurons to extend lifespan. These results reveal lysosomes as a signalling hub to coordinate metabolism and ageing, and lysosomal signalling mediated inter-tissue communication in promoting longevity.
    DOI:  https://doi.org/10.1038/s41556-022-00926-8
  47. Nat Commun. 2022 Jun 07. 13(1): 3275
    Cardiac fibroblasts regulate the development of heart failure via Htra3-TGF-β-IGFBP7 axis.
    Toshiyuki Ko, Seitaro Nomura, Shintaro Yamada, Kanna Fujita, Takanori Fujita, Masahiro Satoh, Chio Oka, Manami Katoh, Masamichi Ito, Mikako Katagiri, Tatsuro Sassa, Bo Zhang, Satoshi Hatsuse, Takanobu Yamada, Mutsuo Harada, Haruhiro Toko, Eisuke Amiya, Masaru Hatano, Osamu Kinoshita, Kan Nawata, Hiroyuki Abe, Tetsuo Ushiku, Minoru Ono, Masashi Ikeuchi, Hiroyuki Morita, Hiroyuki Aburatani, Issei Komuro.
      Tissue fibrosis and organ dysfunction are hallmarks of age-related diseases including heart failure, but it remains elusive whether there is a common pathway to induce both events. Through single-cell RNA-seq, spatial transcriptomics, and genetic perturbation, we elucidate that high-temperature requirement A serine peptidase 3 (Htra3) is a critical regulator of cardiac fibrosis and heart failure by maintaining the identity of quiescent cardiac fibroblasts through degrading transforming growth factor-β (TGF-β). Pressure overload downregulates expression of Htra3 in cardiac fibroblasts and activated TGF-β signaling, which induces not only cardiac fibrosis but also heart failure through DNA damage accumulation and secretory phenotype induction in failing cardiomyocytes. Overexpression of Htra3 in the heart inhibits TGF-β signaling and ameliorates cardiac dysfunction after pressure overload. Htra3-regulated induction of spatio-temporal cardiac fibrosis and cardiomyocyte secretory phenotype are observed specifically in infarct regions after myocardial infarction. Integrative analyses of single-cardiomyocyte transcriptome and plasma proteome in human reveal that IGFBP7, which is a cytokine downstream of TGF-β and secreted from failing cardiomyocytes, is the most predictable marker of advanced heart failure. These findings highlight the roles of cardiac fibroblasts in regulating cardiomyocyte homeostasis and cardiac fibrosis through the Htra3-TGF-β-IGFBP7 pathway, which would be a therapeutic target for heart failure.
    DOI:  https://doi.org/10.1038/s41467-022-30630-y
  48. Cell Metab. 2022 Jun 07. pii: S1550-4131(22)00186-3. [Epub ahead of print]34(6): 919-936.e8
    Inhibition of ATP-citrate lyase improves NASH, liver fibrosis, and dyslipidemia.
    Marisa R Morrow, Battsetseg Batchuluun, Jianhan Wu, Elham Ahmadi, Julie M Leroux, Pedrum Mohammadi-Shemirani, Eric M Desjardins, Zhichao Wang, Evangelia E Tsakiridis, Declan C T Lavoie, Amir Reihani, Brennan K Smith, Jacek M Kwiecien, James S V Lally, Tracy L Nero, Michael W Parker, Kjetil Ask, John W Scott, Lei Jiang, Guillaume Paré, Stephen L Pinkosky, Gregory R Steinberg.
      Elevated liver de novo lipogenesis contributes to non-alcoholic steatohepatitis (NASH) and can be inhibited by targeting acetyl-CoA carboxylase (ACC). However, hypertriglyceridemia limits the use of pharmacological ACC inhibitors as a monotherapy. ATP-citrate lyase (ACLY) generates acetyl-CoA and oxaloacetate from citrate, but whether inhibition is effective for treating NASH is unknown. Here, we characterize a new mouse model that replicates many of the pathological and molecular drivers of NASH and find that genetically inhibiting ACLY in hepatocytes reduces liver malonyl-CoA, oxaloacetate, steatosis, and ballooning as well as blood glucose, triglycerides, and cholesterol. Pharmacological inhibition of ACLY mirrors genetic inhibition but has additional positive effects on hepatic stellate cells, liver inflammation, and fibrosis. Mendelian randomization of human variants that mimic reductions in ACLY also associate with lower circulating triglycerides and biomarkers of NASH. These data indicate that inhibiting liver ACLY may be an effective approach for treatment of NASH and dyslipidemia.
    Keywords:  NASH; cardiovascular disease; diabetes; fatty acid oxidation; gluconeogenesis; hypertriglyceridemia; insulin resistance; lipogenesis; non-alcoholic steatohepatitis; steatosis
    DOI:  https://doi.org/10.1016/j.cmet.2022.05.004
  49. Nat Neurosci. 2022 Jun;25(6): 679-681
    Linking task structure and neural network dynamics.
    Christian David Márton, Siyan Zhou, Kanaka Rajan.
      
    DOI:  https://doi.org/10.1038/s41593-022-01090-w
  50. Nat Commun. 2022 Jun 10. 13(1): 3236
    Excess ribosomal protein production unbalances translation in a model of Fragile X Syndrome.
    Sang S Seo, Susana R Louros, Natasha Anstey, Miguel A Gonzalez-Lozano, Callista B Harper, Nicholas C Verity, Owen Dando, Sophie R Thomson, Jennifer C Darnell, Peter C Kind, Ka Wan Li, Emily K Osterweil.
      Dysregulated protein synthesis is a core pathogenic mechanism in Fragile X Syndrome (FX). The mGluR Theory of FX predicts that pathological synaptic changes arise from the excessive translation of mRNAs downstream of mGlu1/5 activation. Here, we use a combination of CA1 pyramidal neuron-specific TRAP-seq and proteomics to identify the overtranslating mRNAs supporting exaggerated mGlu1/5 -induced long-term synaptic depression (mGluR-LTD) in the FX mouse model (Fmr1-/y). Our results identify a significant increase in the translation of ribosomal proteins (RPs) upon mGlu1/5 stimulation that coincides with a reduced translation of long mRNAs encoding synaptic proteins. These changes are mimicked and occluded in Fmr1-/y neurons. Inhibiting RP translation significantly impairs mGluR-LTD and prevents the length-dependent shift in the translating population. Together, these results suggest that pathological changes in FX result from a length-dependent alteration in the translating population that is supported by excessive RP translation.
    DOI:  https://doi.org/10.1038/s41467-022-30979-0
  51. Nat Rev Genet. 2022 Jun 09.
    tRNA dysregulation and disease.
    Esteban A Orellana, Elisabeth Siegal, Richard I Gregory.
      tRNAs are key adaptor molecules that decipher the genetic code during translation of mRNAs in protein synthesis. In contrast to the traditional view of tRNAs as ubiquitously expressed housekeeping molecules, awareness is now growing that tRNA-encoding genes display tissue-specific and cell type-specific patterns of expression, and that tRNA gene expression and function are both dynamically regulated by post-transcriptional RNA modifications. Moreover, dysregulation of tRNAs, mediated by alterations in either their abundance or function, can have deleterious consequences that contribute to several distinct human diseases, including neurological disorders and cancer. Accumulating evidence shows that reprogramming of mRNA translation through altered tRNA activity can drive pathological processes in a codon-dependent manner. This Review considers the emerging evidence in support of the precise control of functional tRNA levels as an important regulatory mechanism that coordinates mRNA translation and protein expression in physiological cell homeostasis, and highlights key examples of human diseases that are linked directly to tRNA dysregulation.
    DOI:  https://doi.org/10.1038/s41576-022-00501-9
  52. Nat Commun. 2022 Jun 07. 13(1): 3268
    Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes.
    Ji Seul Han, Yong Geun Jeon, Minsik Oh, Gung Lee, Hahn Nahmgoong, Sang Mun Han, Jeehye Choi, Ye Young Kim, Kyung Cheul Shin, Jiwon Kim, Kyuri Jo, Sung Sik Choe, Eun Jung Park, Sun Kim, Jae Bum Kim.
      Thermogenic adipocytes generate heat to maintain body temperature against hypothermia in response to cold. Although tight regulation of thermogenesis is required to prevent energy sources depletion, the molecular details that tune thermogenesis are not thoroughly understood. Here, we demonstrate that adipocyte hypoxia-inducible factor α (HIFα) plays a key role in calibrating thermogenic function upon cold and re-warming. In beige adipocytes, HIFα attenuates protein kinase A (PKA) activity, leading to suppression of thermogenic activity. Mechanistically, HIF2α suppresses PKA activity by inducing miR-3085-3p expression to downregulate PKA catalytic subunit α (PKA Cα). Ablation of adipocyte HIF2α stimulates retention of beige adipocytes, accompanied by increased PKA Cα during re-warming after cold stimuli. Moreover, administration of miR-3085-3p promotes beige-to-white transition via downregulation of PKA Cα and mitochondrial abundance in adipocyte HIF2α deficient mice. Collectively, these findings suggest that HIF2α-dependent PKA regulation plays an important role as a thermostat through dynamic remodeling of beige adipocytes.
    DOI:  https://doi.org/10.1038/s41467-022-30925-0
  53. Nat Commun. 2022 Jun 09. 13(1): 3196
    Proteomic and functional analyses of the periodic membrane skeleton in neurons.
    Ruobo Zhou, Boran Han, Roberta Nowak, Yunzhe Lu, Evan Heller, Chenglong Xia, Athar H Chishti, Velia M Fowler, Xiaowei Zhuang.
      Actin, spectrin, and associated molecules form a membrane-associated periodic skeleton (MPS) in neurons. The molecular composition and functions of the MPS remain incompletely understood. Here, using co-immunoprecipitation and mass spectrometry, we identified hundreds of potential candidate MPS-interacting proteins that span diverse functional categories. We examined representative proteins in several of these categories using super-resolution imaging, including previously unknown MPS structural components, as well as motor proteins, cell adhesion molecules, ion channels, and signaling proteins, and observed periodic distributions characteristic of the MPS along the neurites for ~20 proteins. Genetic perturbations of the MPS and its interacting proteins further suggested functional roles of the MPS in axon-axon and axon-dendrite interactions and in axon diameter regulation, and implicated the involvement of MPS interactions with cell adhesion molecules and non-muscle myosin in these roles. These results provide insights into the interactome of the MPS and suggest previously unknown functions of the MPS in neurons.
    DOI:  https://doi.org/10.1038/s41467-022-30720-x
  54. Nat Biotechnol. 2022 Jun 09.
    CRISPR comes a-knock-in to reprogram antibodies in vivo.
    Harald Hartweger, Michel C Nussenzweig.
      
    DOI:  https://doi.org/10.1038/s41587-022-01299-x
  55. Nat Med. 2022 Jun 06.
    Myths about diversity in clinical trials reduce return on investment for industry.
    Mohammed Suhail Chaudhry, Jessica Spahn, Shilpen Patel, Charles S Fuchs, Jennifer Lauchle, Nikheel Kolatkar, Nicole Richie, Quita Highsmith, Meghan McKenzie, Ruma Bhagat.
      
    DOI:  https://doi.org/10.1038/s41591-022-01858-4
  56. Commun Biol. 2022 Jun 03. 5(1): 541
    GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton.
    Christina Wolf, Alireza Pouya, Sara Bitar, Annika Pfeiffer, Diones Bueno, Liliana Rojas-Charry, Sabine Arndt, David Gomez-Zepeda, Stefan Tenzer, Federica Dal Bello, Caterina Vianello, Sandra Ritz, Jonas Schwirz, Kristina Dobrindt, Michael Peitz, Eva-Maria Hanschmann, Pauline Mencke, Ibrahim Boussaad, Marion Silies, Oliver Brüstle, Marta Giacomello, Rejko Krüger, Axel Methner.
      Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 and beta-tubulin in a redox-dependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. GDAP1 silencing also disrupts mitochondria-ER contact sites. These changes result in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, our findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.
    DOI:  https://doi.org/10.1038/s42003-022-03487-6
  57. Nat Commun. 2022 Jun 09. 13(1): 3224
    Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data.
    Daniel Dimitrov, Dénes Türei, Martin Garrido-Rodriguez, Paul L Burmedi, James S Nagai, Charlotte Boys, Ricardo O Ramirez Flores, Hyojin Kim, Bence Szalai, Ivan G Costa, Alberto Valdeolivas, Aurélien Dugourd, Julio Saez-Rodriguez.
      The growing availability of single-cell data, especially transcriptomics, has sparked an increased interest in the inference of cell-cell communication. Many computational tools were developed for this purpose. Each of them consists of a resource of intercellular interactions prior knowledge and a method to predict potential cell-cell communication events. Yet the impact of the choice of resource and method on the resulting predictions is largely unknown. To shed light on this, we systematically compare 16 cell-cell communication inference resources and 7 methods, plus the consensus between the methods' predictions. Among the resources, we find few unique interactions, a varying degree of overlap, and an uneven coverage of specific pathways and tissue-enriched proteins. We then examine all possible combinations of methods and resources and show that both strongly influence the predicted intercellular interactions. Finally, we assess the agreement of cell-cell communication methods with spatial colocalisation, cytokine activities, and receptor protein abundance and find that predictions are generally coherent with those data modalities. To facilitate the use of the methods and resources described in this work, we provide LIANA, a LIgand-receptor ANalysis frAmework as an open-source interface to all the resources and methods.
    DOI:  https://doi.org/10.1038/s41467-022-30755-0
  58. Cell Death Dis. 2022 Jun 06. 13(6): 531
    Mitochondrial reactive oxygen is critical for IL-12/IL-18-induced IFN-γ production by CD4+ T cells and is regulated by Fas/FasL signaling.
    Gorjana Rackov, Parinaz Tavakoli Zaniani, Sara Colomo Del Pino, Rahman Shokri, Jorge Monserrat, Melchor Alvarez-Mon, Carlos Martinez-A, Dimitrios Balomenos.
      Mitochondrial activation and the production of mitochondrial reactive oxygen species (mROS) are crucial for CD4+ T cell responses and have a role in naïve cell signaling after TCR activation. However, little is known about mROS role in TCR-independent signaling and in recall responses. Here, we found that mROS are required for IL-12 plus IL-18-driven production of IFN-γ, an essential cytokine for inflammatory and autoimmune disease development. Compared to TCR stimulation, which induced similar levels of mROS in naïve and memory-like cells, IL-12/IL-18 showed faster and augmented mROS production in memory-like cells. mROS inhibition significantly downregulated IFN-γ and CD44 expression, suggesting a direct mROS effect on memory-like T cell function. The mechanism that promotes IFN-γ production after IL-12/IL-18 challenge depended on the effect of mROS on optimal activation of downstream signaling pathways, leading to STAT4 and NF-κB activation. To relate our findings to IFN-γ-driven lupus-like disease, we used Fas-deficient memory-like CD4+ T cells from lpr mice. Importantly, we found significantly increased IFN-γ and mROS production in lpr compared with parental cells. Treatment of WT cells with FasL significantly reduced mROS production and the activation of signaling events leading to IFN-γ. Moreover, Fas deficiency was associated with increased mitochondrial levels of cytochrome C and caspase-3 compared with WT memory-like cells. mROS inhibition significantly reduced the population of disease-associated lpr CD44hiCD62LloCD4+ T cells and their IFN-γ production. Overall, these findings uncovered a previously unidentified role of Fas/FasL interaction in regulating mROS production by memory-like T cells. This apoptosis-independent Fas activity might contribute to the accumulation of CD44hiCD62LloCD4+ T cells that produce increased IFN-γ levels in lpr mice. Overall, our findings pinpoint mROS as central regulators of TCR-independent signaling, and support mROS pharmacological targeting to control aberrant immune responses in autoimmune-like disease.
    DOI:  https://doi.org/10.1038/s41419-022-04907-5
  59. Nat Rev Rheumatol. 2022 Jun 10.
    Single-cell RNA sequencing sheds light on cell-type specific gene expression in immune cells.
    Sarah Onuora.
      
    DOI:  https://doi.org/10.1038/s41584-022-00802-7
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