bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–12–03
63 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.
  2. OVOL2 sustains postnatal thymic epithelial cell identity.
  3. Blurring boundaries.
  4. An immune-cell transcription factor tethers DNA together.
  5. The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.
  6. Fragment-sequencing unveils local tissue microenvironments at single-cell resolution.
  7. How human brains differ.
  8. Brain methylome remodeling selectively regulates neuronal activity genes linking to emotional behaviors in mice exposed to maternal immune activation.
  9. FOXP1 and KLF2 reciprocally regulate checkpoints of stem-like to effector transition in CAR T cells.
  10. Mitochondrial DNA editing with mitoARCUS.
  11. Spatial transcriptomics deconvolution at single-cell resolution using Redeconve.
  12. Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease.
  13. Defining a core configuration for human centromeres during mitosis.
  14. scDREAMER for atlas-level integration of single-cell datasets using deep generative model paired with adversarial classifier.
  15. A biology-aware mutation rate model for human germline.
  16. Robust mapping of spatiotemporal trajectories and cell-cell interactions in healthy and diseased tissues.
  17. TScan-II: A genome-scale platform for the de novo identification of CD4+ T cell epitopes.
  18. A mutation rate model at the basepair resolution identifies the mutagenic effect of polymerase III transcription.
  19. PhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants.
  20. COPIng with senescence.
  21. Time-resolved proteomic profiling reveals compositional and functional transitions across the stress granule life cycle.
  22. The rate of epigenetic drift scales with maximum lifespan across mammals.
  23. Intestinal microbiota-specific Th17 cells possess regulatory properties and suppress effector T cells via c-MAF and IL-10.
  24. Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8.
  25. Atomic-level structures show how accuracy is maintained in protein synthesis.
  26. INPP5D regulates inflammasome activation in human microglia.
  27. Human brown fat and metabolic disease: a heated debate.
  28. Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.
  29. Isoform-level transcriptome-wide association uncovers genetic risk mechanisms for neuropsychiatric disorders in the human brain.
  30. BCG vaccination stimulates integrated organ immunity by feedback of the adaptive immune response to imprint prolonged innate antiviral resistance.
  31. Resting-state global brain activity affects early β-amyloid accumulation in default mode network.
  32. LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins.
  33. CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.
  34. An injury-responsive mmp14b enhancer is required for heart regeneration.
  35. iU-ExM: nanoscopy of organelles and tissues with iterative ultrastructure expansion microscopy.
  36. Identification of constrained sequence elements across 239 primate genomes.
  37. A global view of aging and Alzheimer's pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains.
  38. Dbh+ catecholaminergic cardiomyocytes contribute to the structure and function of the cardiac conduction system in murine heart.
  39. Accurate and efficient estimation of local heritability using summary statistics and the linkage disequilibrium matrix.
  40. Human brown adipose tissue is not enough to combat cardiometabolic diseases.
  41. IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling in D-galactose-induced aging mice.
  42. Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.
  43. How carvedilol does not activate β2-adrenoceptors.
  44. The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells.
  45. Mutation hotspots during meiosis.
  46. High-frequency home self-collection of capillary blood correlates IFI27 expression kinetics with SARS-CoV-2 viral clearance.
  47. Mitochondrial E3 ligase MARCH5 is a safeguard against DNA-PKcs-mediated immune signaling in mitochondria-damaged cells.
  48. Associations of myeloid cells with cellular and humoral responses following vaccinations in patients with neuroimmunological diseases.
  49. Haplotype-based inference of recent effective population size in modern and ancient DNA samples.
  50. Adults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01.
  51. Endothelial cell-specific reduction in mTOR ameliorates age-related arterial and metabolic dysfunction.
  52. Pregnant brains in parent mode.
  53. Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis.
  54. PD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma.
  55. The chilling origin of germinal centers.
  56. FOXP3 recognizes microsatellites and bridges DNA through multimerization.
  57. Harnessing T cell exhaustion and trogocytosis to isolate patient-derived tumor-specific TCR.
  58. CurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose-response curves.
  59. Noncanonical MAVS signaling restrains dendritic cell-driven antitumor immunity by inhibiting IL-12.
  60. Myelin and Alzheimer's disease.
  61. Intrinsic factors and CD1d1 but not CD1d2 expression levels control invariant natural killer T cell subset differentiation.
  62. Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.
  63. Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.
  1. Nat Genet. 2023 Nov 30.
    Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution.
    Accelerating Medicines Partnership Program: Rheumatoid Arthritis and Systemic Lupus Erythematosus (AMP RA/SLE) Network
      The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B and T cells. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.
    DOI:  https://doi.org/10.1038/s41588-023-01586-6
  2. Nat Commun. 2023 Nov 27. 14(1): 7786
    OVOL2 sustains postnatal thymic epithelial cell identity.
    Xue Zhong, Nagesh Peddada, Jianhui Wang, James J Moresco, Xiaowei Zhan, John M Shelton, Jeffrey A SoRelle, Katie Keller, Danielle Renee Lazaro, Eva Marie Y Moresco, Jin Huk Choi, Bruce Beutler.
      Distinct pathways and molecules may support embryonic versus postnatal thymic epithelial cell (TEC) development and maintenance. Here, we identify a mechanism by which TEC numbers and function are maintained postnatally. A viable missense allele (C120Y) of Ovol2, expressed ubiquitously or specifically in TECs, results in lymphopenia, in which T cell development is compromised by loss of medullary TECs and dysfunction of cortical TECs. We show that the epithelial identity of TECs is aberrantly subverted towards a mesenchymal state in OVOL2-deficient mice. We demonstrate that OVOL2 inhibits the epigenetic regulatory BRAF-HDAC complex, specifically disrupting RCOR1-LSD1 interaction. This causes inhibition of LSD1-mediated H3K4me2 demethylation, resulting in chromatin accessibility and transcriptional activation of epithelial genes. Thus, OVOL2 controls the epigenetic landscape of TECs to enforce TEC identity. The identification of a non-redundant postnatal mechanism for TEC maintenance offers an entry point to understanding thymic involution, which normally begins in early adulthood.
    DOI:  https://doi.org/10.1038/s41467-023-43456-z
  3. Science. 2023 Dec;382(6674): 1082
    Blurring boundaries.
    Stephanie Sisley.
      
    DOI:  https://doi.org/10.1126/science.adn1127
  4. Nature. 2023 Nov 29.
    An immune-cell transcription factor tethers DNA together.
    Zhi Liu, Ye Zheng.
      
    Keywords:  Genetics; Immunology; Molecular biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-023-03628-9
  5. Nat Commun. 2023 Nov 30. 14(1): 7889
    The poxvirus F17 protein counteracts mitochondrially orchestrated antiviral responses.
    Nathan Meade, Helen K Toreev, Ram P Chakrabarty, Charles R Hesser, Chorong Park, Navdeep S Chandel, Derek Walsh.
      Poxviruses are unusual DNA viruses that replicate in the cytoplasm. To do so, they encode approximately 100 immunomodulatory proteins that counteract cytosolic nucleic acid sensors such as cGAMP synthase (cGAS) along with several other antiviral response pathways. Yet most of these immunomodulators are expressed very early in infection while many are variable host range determinants, and significant gaps remain in our understanding of poxvirus sensing and evasion strategies. Here, we show that after infection is established, subsequent progression of the viral lifecycle is sensed through specific changes to mitochondria that coordinate distinct aspects of the antiviral response. Unlike other viruses that cause extensive mitochondrial damage, poxviruses sustain key mitochondrial functions including membrane potential and respiration while reducing reactive oxygen species that drive inflammation. However, poxvirus replication induces mitochondrial hyperfusion that independently controls the release of mitochondrial DNA (mtDNA) to prime nucleic acid sensors and enables an increase in glycolysis that is necessary to support interferon stimulated gene (ISG) production. To counter this, the poxvirus F17 protein localizes to mitochondria and dysregulates mTOR to simultaneously destabilize cGAS and block increases in glycolysis. Our findings reveal how the poxvirus F17 protein disarms specific mitochondrially orchestrated responses to later stages of poxvirus replication.
    DOI:  https://doi.org/10.1038/s41467-023-43635-y
  6. Nat Commun. 2023 Nov 27. 14(1): 7775
    Fragment-sequencing unveils local tissue microenvironments at single-cell resolution.
    Kristina Handler, Karsten Bach, Costanza Borrelli, Salvatore Piscuoglio, Xenia Ficht, Ilhan E Acar, Andreas E Moor.
      Cells collectively determine biological functions by communicating with each other-both through direct physical contact and secreted factors. Consequently, the local microenvironment of a cell influences its behavior, gene expression, and cellular crosstalk. Disruption of this microenvironment causes reciprocal changes in those features, which can lead to the development and progression of diseases. Hence, assessing the cellular transcriptome while simultaneously capturing the spatial relationships of cells within a tissue provides highly valuable insights into how cells communicate in health and disease. Yet, methods to probe the transcriptome often fail to preserve native spatial relationships, lack single-cell resolution, or are highly limited in throughput, i.e. lack the capacity to assess multiple environments simultaneously. Here, we introduce fragment-sequencing (fragment-seq), a method that enables the characterization of single-cell transcriptomes within multiple spatially distinct tissue microenvironments. We apply fragment-seq to a murine model of the metastatic liver to study liver zonation and the metastatic niche. This analysis reveals zonated genes and ligand-receptor interactions enriched in specific hepatic microenvironments. Finally, we apply fragment-seq to other tissues and species, demonstrating the adaptability of our method.
    DOI:  https://doi.org/10.1038/s41467-023-43005-8
  7. Nat Neurosci. 2023 Dec;26(12): 2048
    How human brains differ.
    Elisa Floriddia.
      
    DOI:  https://doi.org/10.1038/s41593-023-01522-1
  8. Nat Commun. 2023 Nov 29. 14(1): 7829
    Brain methylome remodeling selectively regulates neuronal activity genes linking to emotional behaviors in mice exposed to maternal immune activation.
    Li Ma, Feng Wang, Yangping Li, Jing Wang, Qing Chang, Yuanning Du, Jotham Sadan, Zhen Zhao, Guoping Fan, Bing Yao, Jian-Fu Chen.
      How early life experience is translated into storable epigenetic information leading to behavioral changes remains poorly understood. Here we found that Zika virus (ZIKV) induced-maternal immune activation (MIA) imparts offspring with anxiety- and depression-like behavior. By integrating bulk and single-nucleus RNA sequencing (snRNA-seq) with genome-wide 5hmC (5-hydroxymethylcytosine) profiling and 5mC (5-methylcytosine) profiling in prefrontal cortex (PFC) of ZIKV-affected male offspring mice, we revealed an overall loss of 5hmC and an increase of 5mC levels in intragenic regions, associated with transcriptional changes in neuropsychiatric disorder-related genes. In contrast to their rapid initiation and inactivation in normal conditions, immediate-early genes (IEGs) remain a sustained upregulation with enriched expression in excitatory neurons, which is coupled with increased 5hmC and decreased 5mC levels of IEGs in ZIKV-affected male offspring. Thus, MIA induces maladaptive methylome remodeling in brain and selectively regulates neuronal activity gene methylation linking to emotional behavioral abnormalities in offspring.
    DOI:  https://doi.org/10.1038/s41467-023-43497-4
  9. Nat Immunol. 2023 Nov 27.
    FOXP1 and KLF2 reciprocally regulate checkpoints of stem-like to effector transition in CAR T cells.
    Ziang Zhu, Guohua Lou, Xiao-Lu Teng, Haixia Wang, Ying Luo, Wangke Shi, Kiddist Yihunie, Shumeng Hao, Kole DeGolier, Chengheng Liao, Huocong Huang, Qing Zhang, Terry Fry, Tao Wang, Chen Yao, Tuoqi Wu.
      In cancer and infections, self-renewing stem-like CD8+ T cells mediate the response of immunotherapies and replenish terminally exhausted T cells and effector-like T cells. However, the programs governing the lineage choice in chimeric antigen receptor (CAR) T cells are unclear. Here, by simultaneously profiling single-cell chromatin accessibility and transcriptome in the same CAR T cells, we identified heterogeneous chromatin states within CD8+ T cell subsets that foreshadowed transcriptional changes and were primed for regulation by distinct transcription factors. Transcription factors that controlled each CD8+ T cell subset were regulated by high numbers of enhancers and positioned as hubs of gene networks. FOXP1, a hub in the stem-like network, promoted expansion and stemness of CAR T cells and limited excessive effector differentiation. In the effector network, KLF2 enhanced effector CD8+ T cell differentiation and prevented terminal exhaustion. Thus, we identified gene networks and hub transcription factors that controlled the differentiation of stem-like CD8+ CAR T cells into effector or exhausted CD8+ CAR T cells.
    DOI:  https://doi.org/10.1038/s41590-023-01685-w
  10. Nat Metab. 2023 Nov 30.
    Mitochondrial DNA editing with mitoARCUS.
    Denisa Hathazi, Rita Horvath.
      
    DOI:  https://doi.org/10.1038/s42255-023-00933-5
  11. Nat Commun. 2023 Dec 01. 14(1): 7930
    Spatial transcriptomics deconvolution at single-cell resolution using Redeconve.
    Zixiang Zhou, Yunshan Zhong, Zemin Zhang, Xianwen Ren.
      Computational deconvolution with single-cell RNA sequencing data as reference is pivotal to interpreting spatial transcriptomics data, but the current methods are limited to cell-type resolution. Here we present Redeconve, an algorithm to deconvolute spatial transcriptomics data at single-cell resolution, enabling interpretation of spatial transcriptomics data with thousands of nuanced cell states. We benchmark Redeconve with the state-of-the-art algorithms on diverse spatial transcriptomics platforms and datasets and demonstrate the superiority of Redeconve in terms of accuracy, resolution, robustness, and speed. Application to a human pancreatic cancer dataset reveals cancer-clone-specific T cell infiltration, and application to lymph node samples identifies differential cytotoxic T cells between IgA+ and IgG+ spots, providing novel insights into tumor immunology and the regulatory mechanisms underlying antibody class switch.
    DOI:  https://doi.org/10.1038/s41467-023-43600-9
  12. Nat Commun. 2023 Nov 30. 14(1): 7659
    Cell-type-specific Alzheimer's disease polygenic risk scores are associated with distinct disease processes in Alzheimer's disease.
    Hyun-Sik Yang, Ling Teng, Daniel Kang, Vilas Menon, Tian Ge, Hilary K Finucane, Aaron P Schultz, Michael Properzi, Hans-Ulrich Klein, Lori B Chibnik, Julie A Schneider, David A Bennett, Timothy J Hohman, Richard P Mayeux, Keith A Johnson, Philip L De Jager, Reisa A Sperling.
      Many of the Alzheimer's disease (AD) risk genes are specifically expressed in microglia and astrocytes, but how and when the genetic risk localizing to these cell types contributes to AD pathophysiology remains unclear. Here, we derive cell-type-specific AD polygenic risk scores (ADPRS) from two extensively characterized datasets and uncover the impact of cell-type-specific genetic risk on AD endophenotypes. In an autopsy dataset spanning all stages of AD (n = 1457), the astrocytic ADPRS affected diffuse and neuritic plaques (amyloid-β), while microglial ADPRS affected neuritic plaques, microglial activation, neurofibrillary tangles (tau), and cognitive decline. In an independent neuroimaging dataset of cognitively unimpaired elderly (n = 2921), astrocytic ADPRS was associated with amyloid-β, and microglial ADPRS was associated with amyloid-β and tau, connecting cell-type-specific genetic risk with AD pathology even before symptom onset. Together, our study provides human genetic evidence implicating multiple glial cell types in AD pathophysiology, starting from the preclinical stage.
    DOI:  https://doi.org/10.1038/s41467-023-43132-2
  13. Nat Commun. 2023 Dec 01. 14(1): 7947
    Defining a core configuration for human centromeres during mitosis.
    Ayantika Sen Gupta, Chris Seidel, Dai Tsuchiya, Sean McKinney, Zulin Yu, Sarah E Smith, Jay R Unruh, Jennifer L Gerton.
      The centromere components cohesin, CENP-A, and centromeric DNA are essential for biorientation of sister chromatids on the mitotic spindle and accurate sister chromatid segregation. Insight into the 3D organization of centromere components would help resolve how centromeres function on the mitotic spindle. We use ChIP-seq and super-resolution microscopy with single particle averaging to examine the geometry of essential centromeric components on human chromosomes. Both modalities suggest cohesin is enriched at pericentromeric DNA. CENP-A localizes to a subset of the α-satellite DNA, with clusters separated by ~562 nm and a perpendicular intervening ~190 nM wide axis of cohesin in metaphase chromosomes. Differently sized α-satellite arrays achieve a similar core structure. Here we present a working model for a common core configuration of essential centromeric components that includes CENP-A nucleosomes, α-satellite DNA and pericentromeric cohesion. This configuration helps reconcile how centromeres function and serves as a foundation to add components of the chromosome segregation machinery.
    DOI:  https://doi.org/10.1038/s41467-023-42980-2
  14. Nat Commun. 2023 Nov 27. 14(1): 7781
    scDREAMER for atlas-level integration of single-cell datasets using deep generative model paired with adversarial classifier.
    Ajita Shree, Musale Krushna Pavan, Hamim Zafar.
      Integration of heterogeneous single-cell sequencing datasets generated across multiple tissue locations, time, and conditions is essential for a comprehensive understanding of the cellular states and expression programs underlying complex biological systems. Here, we present scDREAMER ( https://github.com/Zafar-Lab/scDREAMER ), a data-integration framework that employs deep generative models and adversarial training for both unsupervised and supervised (scDREAMER-Sup) integration of multiple batches. Using six real benchmarking datasets, we demonstrate that scDREAMER can overcome critical challenges including skewed cell type distribution among batches, nested batch-effects, large number of batches and conservation of development trajectory across batches. Our experiments also show that scDREAMER and scDREAMER-Sup outperform state-of-the-art unsupervised and supervised integration methods respectively in batch-correction and conservation of biological variation. Using a 1 million cells dataset, we demonstrate that scDREAMER is scalable and can perform atlas-level cross-species (e.g., human and mouse) integration while being faster than other deep-learning-based methods.
    DOI:  https://doi.org/10.1038/s41467-023-43590-8
  15. Nat Genet. 2023 Dec 01.
    A biology-aware mutation rate model for human germline.
      
    DOI:  https://doi.org/10.1038/s41588-023-01564-y
  16. Nat Commun. 2023 Nov 25. 14(1): 7739
    Robust mapping of spatiotemporal trajectories and cell-cell interactions in healthy and diseased tissues.
    Duy Pham, Xiao Tan, Brad Balderson, Jun Xu, Laura F Grice, Sohye Yoon, Emily F Willis, Minh Tran, Pui Yeng Lam, Arti Raghubar, Priyakshi Kalita-de Croft, Sunil Lakhani, Jana Vukovic, Marc J Ruitenberg, Quan H Nguyen.
      Spatial transcriptomics (ST) technologies generate multiple data types from biological samples, namely gene expression, physical distance between data points, and/or tissue morphology. Here we developed three computational-statistical algorithms that integrate all three data types to advance understanding of cellular processes. First, we present a spatial graph-based method, pseudo-time-space (PSTS), to model and uncover relationships between transcriptional states of cells across tissues undergoing dynamic change (e.g. neurodevelopment, brain injury and/or microglia activation, and cancer progression). We further developed a spatially-constrained two-level permutation (SCTP) test to study cell-cell interaction, finding highly interactive tissue regions across thousands of ligand-receptor pairs with markedly reduced false discovery rates. Finally, we present a spatial graph-based imputation method with neural network (stSME), to correct for technical noise/dropout and increase ST data coverage. Together, the algorithms that we developed, implemented in the comprehensive and fast stLearn software, allow for robust interrogation of biological processes within healthy and diseased tissues.
    DOI:  https://doi.org/10.1038/s41467-023-43120-6
  17. Cell. 2023 Nov 16. pii: S0092-8674(23)01175-3. [Epub ahead of print]
    TScan-II: A genome-scale platform for the de novo identification of CD4+ T cell epitopes.
    Mohammad H Dezfulian, Tomasz Kula, Thomas Pranzatelli, Nolan Kamitaki, Qingda Meng, Bhuwan Khatri, Paola Perez, Qikai Xu, Aiquan Chang, Ayano C Kohlgruber, Yumei Leng, Ananth Aditya Jupudi, Michelle L Joachims, John A Chiorini, Christopher J Lessard, A Darise Farris, Senthil K Muthuswamy, Blake M Warner, Stephen J Elledge.
      CD4+ T cells play fundamental roles in orchestrating immune responses and tissue homeostasis. However, our inability to associate peptide human leukocyte antigen class-II (HLA-II) complexes with their cognate T cell receptors (TCRs) in an unbiased manner has hampered our understanding of CD4+ T cell function and role in pathologies. Here, we introduce TScan-II, a highly sensitive genome-scale CD4+ antigen discovery platform. This platform seamlessly integrates the endogenous HLA-II antigen-processing machinery in synthetic antigen-presenting cells and TCR signaling in T cells, enabling the simultaneous screening of multiple HLAs and TCRs. Leveraging genome-scale human, virome, and epitope mutagenesis libraries, TScan-II facilitates de novo antigen discovery and deep exploration of TCR specificity. We demonstrate TScan-II's potential for basic and translational research by identifying a non-canonical antigen for a cancer-reactive CD4+ T cell clone. Additionally, we identified two antigens for clonally expanded CD4+ T cells in Sjögren's disease, which bind distinct HLAs and are expressed in HLA-II-positive ductal cells within affected salivary glands.
    Keywords:  CD4+ T cell; HIV; Pancreatic cancer; Sjögren’s disease; T cell epitope; T cell screening; antigen discovery; antigen library; epitope discovery; epitope mutagenesis
    DOI:  https://doi.org/10.1016/j.cell.2023.10.024
  18. Nat Genet. 2023 Nov 30.
    A mutation rate model at the basepair resolution identifies the mutagenic effect of polymerase III transcription.
    Vladimir Seplyarskiy, Evan M Koch, Daniel J Lee, Joshua S Lichtman, Harding H Luan, Shamil R Sunyaev.
      De novo mutations occur at substantially different rates depending on genomic location, sequence context and DNA strand. The success of methods to estimate selection intensity, infer demographic history and map rare disease genes, depends strongly on assumptions about the local mutation rate. Here we present Roulette, a genome-wide mutation rate model at basepair resolution that incorporates known determinants of local mutation rate. Roulette is shown to be more accurate than existing models. We use Roulette to refine the estimates of population growth within Europe by incorporating the full range of human mutation rates. The analysis of significant deviations from the model predictions revealed a tenfold increase in mutation rate in nearly all genes transcribed by polymerase III (Pol III), suggesting a new mutagenic mechanism. We also detected an elevated mutation rate within transcription factor binding sites restricted to sites actively used in testis and residing in promoters.
    DOI:  https://doi.org/10.1038/s41588-023-01562-0
  19. Nat Commun. 2023 Nov 28. 14(1): 7805
    PhenoSV: interpretable phenotype-aware model for the prioritization of genes affected by structural variants.
    Zhuoran Xu, Quan Li, Luigi Marchionni, Kai Wang.
      Structural variants (SVs) represent a major source of genetic variation associated with phenotypic diversity and disease susceptibility. While long-read sequencing can discover over 20,000 SVs per human genome, interpreting their functional consequences remains challenging. Existing methods for identifying disease-related SVs focus on deletion/duplication only and cannot prioritize individual genes affected by SVs, especially for noncoding SVs. Here, we introduce PhenoSV, a phenotype-aware machine-learning model that interprets all major types of SVs and genes affected. PhenoSV segments and annotates SVs with diverse genomic features and employs a transformer-based architecture to predict their impacts under a multiple-instance learning framework. With phenotype information, PhenoSV further utilizes gene-phenotype associations to prioritize phenotype-related SVs. Evaluation on extensive human SV datasets covering all SV types demonstrates PhenoSV's superior performance over competing methods. Applications in diseases suggest that PhenoSV can determine disease-related genes from SVs. A web server and a command-line tool for PhenoSV are available at https://phenosv.wglab.org .
    DOI:  https://doi.org/10.1038/s41467-023-43651-y
  20. Nat Cell Biol. 2023 Nov 27.
    COPIng with senescence.
    Stella Victorelli, João F Passos.
      
    DOI:  https://doi.org/10.1038/s41556-023-01276-9
  21. Nat Commun. 2023 Nov 27. 14(1): 7782
    Time-resolved proteomic profiling reveals compositional and functional transitions across the stress granule life cycle.
    Shuyao Hu, Yufeng Zhang, Qianqian Yi, Cuiwei Yang, Yanfen Liu, Yun Bai.
      Stress granules (SGs) are dynamic, membrane-less organelles. With their formation and disassembly processes characterized, it remains elusive how compositional transitions are coordinated during prolonged stress to meet changing functional needs. Here, using time-resolved proteomic profiling of the acute to prolonged heat-shock SG life cycle, we identify dynamic SG proteins, further segregated into early and late proteins. Comparison of different groups of SG proteins suggests that their biochemical properties help coordinate SG compositional and functional transitions. In particular, early proteins, with high phase-separation-propensity, drive the rapid formation of the initial SG platform, while late proteins are subsequently recruited as discrete modules to further functionalize SGs. This model, supported by immunoblotting and immunofluorescence imaging, provides a conceptual framework for the compositional transitions throughout the acute to prolonged SG life cycle. Additionally, an early SG constituent, non-muscle myosin II, is shown to promote SG formation by increasing SG fusion, underscoring the strength of this dataset in revealing the complexity of SG regulation.
    DOI:  https://doi.org/10.1038/s41467-023-43470-1
  22. Nat Commun. 2023 Nov 25. 14(1): 7731
    The rate of epigenetic drift scales with maximum lifespan across mammals.
    Emily M Bertucci-Richter, Benjamin B Parrott.
      Epigenetic drift or "disorder" increases across the mouse lifespan and is suggested to underlie epigenetic clock signals. While the role of epigenetic drift in determining maximum lifespan across species has been debated, robust tests of this hypothesis are lacking. Here, we test if epigenetic disorder at various levels of genomic resolution explains maximum lifespan across four mammal species. We show that epigenetic disorder increases with age in all species and at all levels of genomic resolution tested. The rate of disorder accumulation occurs faster in shorter lived species and corresponds to species adjusted maximum lifespan. While the density of cytosine-phosphate-guanine dinucleotides ("CpGs") is negatively associated with the rate of age-associated disorder accumulation, it does not fully explain differences across species. Our findings support the hypothesis that the rate of epigenetic drift explains maximum lifespan and provide partial support for the hypothesis that CpG density buffers against epigenetic drift.
    DOI:  https://doi.org/10.1038/s41467-023-43417-6
  23. Immunity. 2023 Nov 29. pii: S1074-7613(23)00484-3. [Epub ahead of print]
    Intestinal microbiota-specific Th17 cells possess regulatory properties and suppress effector T cells via c-MAF and IL-10.
    Leonie Brockmann, Alexander Tran, Yiming Huang, Madeline Edwards, Carlotta Ronda, Harris H Wang, Ivaylo I Ivanov.
      Commensal microbes induce cytokine-producing effector tissue-resident CD4+ T cells, but the function of these T cells in mucosal homeostasis is not well understood. Here, we report that commensal-specific intestinal Th17 cells possess an anti-inflammatory phenotype marked by expression of interleukin (IL)-10 and co-inhibitory receptors. The anti-inflammatory phenotype of gut-resident commensal-specific Th17 cells was driven by the transcription factor c-MAF. IL-10-producing commensal-specific Th17 cells were heterogeneous and derived from a TCF1+ gut-resident progenitor Th17 cell population. Th17 cells acquired IL-10 expression and anti-inflammatory phenotype in the small-intestinal lamina propria. IL-10 production by CD4+ T cells and IL-10 signaling in intestinal macrophages drove IL-10 expression by commensal-specific Th17 cells. Intestinal commensal-specific Th17 cells possessed immunoregulatory functions and curbed effector T cell activity in vitro and in vivo in an IL-10-dependent and c-MAF-dependent manner. Our results suggest that tissue-resident commensal-specific Th17 cells perform regulatory functions in mucosal homeostasis.
    Keywords:  IL-10; TCF1; Th17 cells; Treg; c-MAF; commensal-specific CD4 T cells; intestine; microbiota; mucosal immunology; segmented filamentous bacteria
    DOI:  https://doi.org/10.1016/j.immuni.2023.11.003
  24. Nat Commun. 2023 Dec 01. 14(1): 7940
    Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8.
    Dawei Sun, Yonglian Sun, Eric Janezic, Tricia Zhou, Matthew Johnson, Caleigh Azumaya, Sigrid Noreng, Cecilia Chiu, Akiko Seki, Teresita L Arenzana, John M Nicoludis, Yongchang Shi, Baomei Wang, Hoangdung Ho, Prajakta Joshi, Christine Tam, Jian Payandeh, Laëtitia Comps-Agrar, Jianyong Wang, Sascha Rutz, James T Koerber, Matthieu Masureel.
      The C-C motif chemokine receptor 8 (CCR8) is a class A G-protein coupled receptor that has emerged as a promising therapeutic target in cancer. Targeting CCR8 with an antibody has appeared to be an attractive therapeutic approach, but the molecular basis for chemokine-mediated activation and antibody-mediated inhibition of CCR8 are not fully elucidated. Here, we obtain an antagonist antibody against human CCR8 and determine structures of CCR8 in complex with either the antibody or the endogenous agonist ligand CCL1. Our studies reveal characteristic antibody features allowing recognition of the CCR8 extracellular loops and CCL1-CCR8 interaction modes that are distinct from other chemokine receptor - ligand pairs. Informed by these structural insights, we demonstrate that CCL1 follows a two-step, two-site binding sequence to CCR8 and that antibody-mediated inhibition of CCL1 signaling can occur by preventing the second binding event. Together, our results provide a detailed structural and mechanistic framework of CCR8 activation and inhibition that expands our molecular understanding of chemokine - receptor interactions and offers insight into the development of therapeutic antibodies targeting chemokine GPCRs.
    DOI:  https://doi.org/10.1038/s41467-023-43601-8
  25. Nature. 2023 Nov 29.
    Atomic-level structures show how accuracy is maintained in protein synthesis.
      
    Keywords:  Biochemistry; Microscopy; Structural biology
    DOI:  https://doi.org/10.1038/d41586-023-03382-y
  26. Nat Commun. 2023 Nov 29. 14(1): 7552
    INPP5D regulates inflammasome activation in human microglia.
    Vicky Chou, Richard V Pearse, Aimee J Aylward, Nancy Ashour, Mariko Taga, Gizem Terzioglu, Masashi Fujita, Seeley B Fancher, Alina Sigalov, Courtney R Benoit, Hyo Lee, Matti Lam, Nicholas T Seyfried, David A Bennett, Philip L De Jager, Vilas Menon, Tracy L Young-Pearse.
      Microglia and neuroinflammation play an important role in the development and progression of Alzheimer's disease (AD). Inositol polyphosphate-5-phosphatase D (INPP5D/SHIP1) is a myeloid-expressed gene genetically-associated with AD. Through unbiased analyses of RNA and protein profiles in INPP5D-disrupted iPSC-derived human microglia, we find that reduction in INPP5D activity is associated with molecular profiles consistent with disrupted autophagy and inflammasome activation. These findings are validated through targeted pharmacological experiments which demonstrate that reduced INPP5D activity induces the formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1β and IL-18. Further, in-depth analyses of human brain tissue across hundreds of individuals using a multi-analytic approach provides evidence that a reduction in function of INPP5D in microglia results in inflammasome activation in AD. These findings provide insights into the molecular mechanisms underlying microglia-mediated processes in AD and highlight the inflammasome as a potential therapeutic target for modulating INPP5D-mediated vulnerability to AD.
    DOI:  https://doi.org/10.1038/s41467-023-42819-w
  27. J Clin Invest. 2023 Dec 01. pii: e176678. [Epub ahead of print]133(23):
    Human brown fat and metabolic disease: a heated debate.
    Rana K Gupta.
      
    DOI:  https://doi.org/10.1172/JCI176678
  28. J Immunol. 2023 Dec 01. pii: ji2200835. [Epub ahead of print]
    Cutting Edge: STING Induces ACLY Activation and Metabolic Adaptations in Human Macrophages through TBK1.
    Maximilian Nickenig, Matthew S J Mangan, Hye Eun Lee, Konstantinos Symeonidis, Antonia Henne, Romina Kaiser, Eike Geißmar, Hendrikus Garritsen, Zeinab Abdullah, Karsten Hiller, Eicke Latz, Mario A Lauterbach.
      The 2'3'-cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of IFN genes (STING) pathway can sense infection and cellular stress by detecting cytosolic DNA. Upon ligand binding, cGAS produces the cyclic dinucleotide messenger cGAMP, which triggers its receptor STING. Active STING initiates gene transcription through the transcription factors IFN regulatory factor 3 (IRF3) and NF-κB and induces autophagy, but whether STING can cause changes in the metabolism of macrophages is unknown. In this study, we report that STING signaling activates ATP-citrate lyase (ACLY) by phosphorylation in human macrophages. Using genetic and pharmacologic perturbation, we show that STING targets ACLY via its prime downstream signaling effector TANK (TRAF family member-associated NF-κB activator)-binding kinase 1 (TBK1). We further identify that TBK1 alters cellular metabolism upon cGAMP treatment. Our results suggest that STING-mediated metabolic reprogramming adjusts the cellular response to DNA sensing in addition to transcription factor activation and autophagy induction.
    DOI:  https://doi.org/10.4049/jimmunol.2200835
  29. Nat Genet. 2023 Nov 30.
    Isoform-level transcriptome-wide association uncovers genetic risk mechanisms for neuropsychiatric disorders in the human brain.
    Arjun Bhattacharya, Daniel D Vo, Connor Jops, Minsoo Kim, Cindy Wen, Jonatan L Hervoso, Bogdan Pasaniuc, Michael J Gandal.
      Methods integrating genetics with transcriptomic reference panels prioritize risk genes and mechanisms at only a fraction of trait-associated genetic loci, due in part to an overreliance on total gene expression as a molecular outcome measure. This challenge is particularly relevant for the brain, in which extensive splicing generates multiple distinct transcript-isoforms per gene. Due to complex correlation structures, isoform-level modeling from cis-window variants requires methodological innovation. Here we introduce isoTWAS, a multivariate, stepwise framework integrating genetics, isoform-level expression and phenotypic associations. Compared to gene-level methods, isoTWAS improves both isoform and gene expression prediction, yielding more testable genes, and increased power for discovery of trait associations within genome-wide association study loci across 15 neuropsychiatric traits. We illustrate multiple isoTWAS associations undetectable at the gene-level, prioritizing isoforms of AKT3, CUL3 and HSPD1 in schizophrenia and PCLO with multiple disorders. Results highlight the importance of incorporating isoform-level resolution within integrative approaches to increase discovery of trait associations, especially for brain-relevant traits.
    DOI:  https://doi.org/10.1038/s41588-023-01560-2
  30. Nat Immunol. 2023 Nov 30.
    BCG vaccination stimulates integrated organ immunity by feedback of the adaptive immune response to imprint prolonged innate antiviral resistance.
    Audrey Lee, Katharine Floyd, Shengyang Wu, Zhuoqing Fang, Tze Kai Tan, Heather M Froggatt, John M Powers, Sarah R Leist, Kendra L Gully, Miranda L Hubbard, Chunfeng Li, Harold Hui, David Scoville, Alistaire D Ruggiero, Yan Liang, Anna Pavenko, Victor Lujan, Ralph S Baric, Garry P Nolan, Prabhu S Arunachalam, Mehul S Suthar, Bali Pulendran.
      Bacille Calmette-Guérin (BCG) vaccination can confer nonspecific protection against heterologous pathogens. However, the underlying mechanisms remain mysterious. We show that mice vaccinated intravenously with BCG exhibited reduced weight loss and/or improved viral clearance when challenged with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 B.1.351) or PR8 influenza. Protection was first evident between 14 and 21 d post-vaccination and lasted ∼3 months. Notably, BCG induced a biphasic innate response and robust antigen-specific type 1 helper T cell (TH1 cell) responses in the lungs. MyD88 signaling was essential for innate and TH1 cell responses, and protection against SARS-CoV-2. Depletion of CD4+ T cells or interferon (IFN)-γ activity before infection obliterated innate activation and protection. Single-cell and spatial transcriptomics revealed CD4-dependent expression of IFN-stimulated genes in lung myeloid and epithelial cells. Notably, BCG also induced protection against weight loss after mouse-adapted SARS-CoV-2 BA.5, SARS-CoV and SHC014 coronavirus infections. Thus, BCG elicits integrated organ immunity, where CD4+ T cells feed back on tissue myeloid and epithelial cells to imprint prolonged and broad innate antiviral resistance.
    DOI:  https://doi.org/10.1038/s41590-023-01700-0
  31. Nat Commun. 2023 Nov 27. 14(1): 7788
    Resting-state global brain activity affects early β-amyloid accumulation in default mode network.
    Feng Han, Xufu Liu, Richard B Mailman, Xuemei Huang, Xiao Liu.
      It remains unclear why β-amyloid (Aβ) plaque, a hallmark pathology of Alzheimer's disease (AD), first accumulates cortically in the default mode network (DMN), years before AD diagnosis. Resting-state low-frequency ( < 0.1 Hz) global brain activity recently was linked to AD, presumably due to its role in glymphatic clearance. Here we show that the preferential Aβ accumulation in the DMN at the early stage of Aβ pathology was associated with the preferential reduction of global brain activity in the same regions. This can be partly explained by its failure to reach these regions as propagating waves. Together, these findings highlight the important role of resting-state global brain activity in early preferential Aβ deposition in the DMN.
    DOI:  https://doi.org/10.1038/s41467-023-43627-y
  32. Nat Commun. 2023 Nov 27. 14(1): 7774
    LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins.
    T Bertie Ansell, Wanling Song, Claire E Coupland, Loic Carrique, Robin A Corey, Anna L Duncan, C Keith Cassidy, Maxwell M G Geurts, Tim Rasmussen, Andrew B Ward, Christian Siebold, Phillip J Stansfeld, Mark S P Sansom.
      Cryo-electron microscopy (cryo-EM) enables the determination of membrane protein structures in native-like environments. Characterising how membrane proteins interact with the surrounding membrane lipid environment is assisted by resolution of lipid-like densities visible in cryo-EM maps. Nevertheless, establishing the molecular identity of putative lipid and/or detergent densities remains challenging. Here we present LipIDens, a pipeline for molecular dynamics (MD) simulation-assisted interpretation of lipid and lipid-like densities in cryo-EM structures. The pipeline integrates the implementation and analysis of multi-scale MD simulations for identification, ranking and refinement of lipid binding poses which superpose onto cryo-EM map densities. Thus, LipIDens enables direct integration of experimental and computational structural approaches to facilitate the interpretation of lipid-like cryo-EM densities and to reveal the molecular identities of protein-lipid interactions within a bilayer environment. We demonstrate this by application of our open-source LipIDens code to ten diverse membrane protein structures which exhibit lipid-like densities.
    DOI:  https://doi.org/10.1038/s41467-023-43392-y
  33. Nat Commun. 2023 Nov 29. 14(1): 7824
    CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice.
    Philipp Hammerschmidt, Sophie M Steculorum, Cécile L Bandet, Almudena Del Río-Martín, Lukas Steuernagel, Vivien Kohlhaas, Marvin Feldmann, Luis Varela, Adam Majcher, Marta Quatorze Correia, Rhena F U Klar, Corinna A Bauder, Ecem Kaya, Marta Porniece, Nasim Biglari, Anna Sieben, Tamas L Horvath, Thorsten Hornemann, Susanne Brodesser, Jens C Brüning.
      Dysregulation of hypothalamic ceramides has been associated with disrupted neuronal pathways in control of energy and glucose homeostasis. However, the specific ceramide species promoting neuronal lipotoxicity in obesity have remained obscure. Here, we find increased expression of the C16:0 ceramide-producing ceramide synthase (CerS)6 in cultured hypothalamic neurons exposed to palmitate in vitro and in the hypothalamus of obese mice. Conditional deletion of CerS6 in hypothalamic neurons attenuates high-fat diet (HFD)-dependent weight gain and improves glucose metabolism. Specifically, CerS6 deficiency in neurons expressing pro-opiomelanocortin (POMC) or steroidogenic factor 1 (SF-1) alters feeding behavior and alleviates the adverse metabolic effects of HFD feeding on insulin sensitivity and glucose tolerance. POMC-expressing cell-selective deletion of CerS6 prevents the diet-induced alterations of mitochondrial morphology and improves cellular leptin sensitivity. Our experiments reveal functions of CerS6-derived ceramides in hypothalamic lipotoxicity, altered mitochondrial dynamics, and ER/mitochondrial stress in the deregulation of food intake and glucose metabolism in obesity.
    DOI:  https://doi.org/10.1038/s41467-023-42595-7
  34. Sci Adv. 2023 Dec;9(48): eadh5313
    An injury-responsive mmp14b enhancer is required for heart regeneration.
    Ivana Zlatanova, Fei Sun, Roland S Wu, Xiaoxin Chen, Bryan H Lau, Pauline Colombier, Tanvi Sinha, Barbara Celona, Shan-Mei Xu, Stefan C Materna, Guo N Huang, Brian L Black.
      Mammals have limited capacity for heart regeneration, whereas zebrafish have extraordinary regeneration abilities. During zebrafish heart regeneration, endothelial cells promote cardiomyocyte cell cycle reentry and myocardial repair, but the mechanisms responsible for promoting an injury microenvironment conducive to regeneration remain incompletely defined. Here, we identify the matrix metalloproteinase Mmp14b as an essential regulator of heart regeneration. We identify a TEAD-dependent mmp14b endothelial enhancer induced by heart injury in zebrafish and mice, and we show that the enhancer is required for regeneration, supporting a role for Hippo signaling upstream of mmp14b. Last, we show that MMP-14 function in mice is important for the accumulation of Agrin, an essential regulator of neonatal mouse heart regeneration. These findings reveal mechanisms for extracellular matrix remodeling that promote heart regeneration.
    DOI:  https://doi.org/10.1126/sciadv.adh5313
  35. Nat Commun. 2023 Nov 30. 14(1): 7893
    iU-ExM: nanoscopy of organelles and tissues with iterative ultrastructure expansion microscopy.
    Vincent Louvel, Romuald Haase, Olivier Mercey, Marine H Laporte, Thibaut Eloy, Étienne Baudrier, Denis Fortun, Dominique Soldati-Favre, Virginie Hamel, Paul Guichard.
      Expansion microscopy (ExM) is a highly effective technique for super-resolution fluorescence microscopy that enables imaging of biological samples beyond the diffraction limit with conventional fluorescence microscopes. Despite the development of several enhanced protocols, ExM has not yet demonstrated the ability to achieve the precision of nanoscopy techniques such as Single Molecule Localization Microscopy (SMLM). Here, to address this limitation, we have developed an iterative ultrastructure expansion microscopy (iU-ExM) approach that achieves SMLM-level resolution. With iU-ExM, it is now possible to visualize the molecular architecture of gold-standard samples, such as the eight-fold symmetry of nuclear pores or the molecular organization of the conoid in Apicomplexa. With its wide-ranging applications, from isolated organelles to cells and tissue, iU-ExM opens new super-resolution avenues for scientists studying biological structures and functions.
    DOI:  https://doi.org/10.1038/s41467-023-43582-8
  36. Nature. 2023 Nov 29.
    Identification of constrained sequence elements across 239 primate genomes.
    Lukas F K Kuderna, Jacob C Ulirsch, Sabrina Rashid, Mohamed Ameen, Laksshman Sundaram, Glenn Hickey, Anthony J Cox, Hong Gao, Arvind Kumar, Francois Aguet, Matthew J Christmas, Hiram Clawson, Maximilian Haeussler, Mareike C Janiak, Martin Kuhlwilm, Joseph D Orkin, Thomas Bataillon, Shivakumara Manu, Alejandro Valenzuela, Juraj Bergman, Marjolaine Rouselle, Felipe Ennes Silva, Lidia Agueda, Julie Blanc, Marta Gut, Dorien de Vries, Ian Goodhead, R Alan Harris, Muthuswamy Raveendran, Axel Jensen, Idriss S Chuma, Julie E Horvath, Christina Hvilsom, David Juan, Peter Frandsen, Joshua G Schraiber, Fabiano R de Melo, Fabrício Bertuol, Hazel Byrne, Iracilda Sampaio, Izeni Farias, João Valsecchi, Malu Messias, Maria N F da Silva, Mihir Trivedi, Rogerio Rossi, Tomas Hrbek, Nicole Andriaholinirina, Clément J Rabarivola, Alphonse Zaramody, Clifford J Jolly, Jane Phillips-Conroy, Gregory Wilkerson, Christian Abee, Joe H Simmons, Eduardo Fernandez-Duque, Sree Kanthaswamy, Fekadu Shiferaw, Dongdong Wu, Long Zhou, Yong Shao, Guojie Zhang, Julius D Keyyu, Sascha Knauf, Minh D Le, Esther Lizano, Stefan Merker, Arcadi Navarro, Tilo Nadler, Chiea Chuen Khor, Jessica Lee, Patrick Tan, Weng Khong Lim, Andrew C Kitchener, Dietmar Zinner, Ivo Gut, Amanda D Melin, Katerina Guschanski, Mikkel Heide Schierup, Robin M D Beck, Ioannis Karakikes, Kevin C Wang, Govindhaswamy Umapathy, Christian Roos, Jean P Boubli, Adam Siepel, Anshul Kundaje, Benedict Paten, Kerstin Lindblad-Toh, Jeffrey Rogers, Tomas Marques Bonet, Kyle Kai-How Farh.
      Noncoding DNA is central to our understanding of human gene regulation and complex diseases1,2, and measuring the evolutionary sequence constraint can establish the functional relevance of putative regulatory elements in the human genome3-9. Identifying the genomic elements that have become constrained specifically in primates has been hampered by the faster evolution of noncoding DNA compared to protein-coding DNA10, the relatively short timescales separating primate species11, and the previously limited availability of whole-genome sequences12. Here we construct a whole-genome alignment of 239 species, representing nearly half of all extant species in the primate order. Using this resource, we identified human regulatory elements that are under selective constraint across primates and other mammals at a 5% false discovery rate. We detected 111,318 DNase I hypersensitivity sites and 267,410 transcription factor binding sites that are constrained specifically in primates but not across other placental mammals and validate their cis-regulatory effects on gene expression. These regulatory elements are enriched for human genetic variants that affect gene expression and complex traits and diseases. Our results highlight the important role of recent evolution in regulatory sequence elements differentiating primates, including humans, from other placental mammals.
    DOI:  https://doi.org/10.1038/s41586-023-06798-8
  37. Nat Genet. 2023 Nov 30.
    A global view of aging and Alzheimer's pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains.
    Andras Sziraki, Ziyu Lu, Jasper Lee, Gabor Banyai, Sonya Anderson, Abdulraouf Abdulraouf, Eli Metzner, Andrew Liao, Jason Banfelder, Alexander Epstein, Chloe Schaefer, Zihan Xu, Zehao Zhang, Li Gan, Peter T Nelson, Wei Zhou, Junyue Cao.
      Conventional methods fall short in unraveling the dynamics of rare cell types related to aging and diseases. Here we introduce EasySci, an advanced single-cell combinatorial indexing strategy for exploring age-dependent cellular dynamics in the mammalian brain. Profiling approximately 1.5 million single-cell transcriptomes and 400,000 chromatin accessibility profiles across diverse mouse brains, we identified over 300 cell subtypes, uncovering their molecular characteristics and spatial locations. This comprehensive view elucidates rare cell types expanded or depleted upon aging. We also investigated cell-type-specific responses to genetic alterations linked to Alzheimer's disease, identifying associated rare cell types. Additionally, by profiling 118,240 human brain single-cell transcriptomes, we discerned cell- and region-specific transcriptomic changes tied to Alzheimer's pathogenesis. In conclusion, this research offers a valuable resource for probing cell-type-specific dynamics in both normal and pathological aging.
    DOI:  https://doi.org/10.1038/s41588-023-01572-y
  38. Nat Commun. 2023 Nov 28. 14(1): 7801
    Dbh+ catecholaminergic cardiomyocytes contribute to the structure and function of the cardiac conduction system in murine heart.
    Tianyi Sun, Alexander Grassam-Rowe, Zhaoli Pu, Yangpeng Li, Huiying Ren, Yanru An, Xinyu Guo, Wei Hu, Ying Liu, Yuqing Zheng, Zhu Liu, Kun Kou, Xianhong Ou, Tangting Chen, Xuehui Fan, Yangyang Liu, Shu Tu, Yu He, Yue Ren, Ao Chen, Zhouchun Shang, Zhidao Xia, Lucile Miquerol, Nicola Smart, Henggui Zhang, Xiaoqiu Tan, Weinian Shou, Ming Lei.
      The heterogeneity of functional cardiomyocytes arises during heart development, which is essential to the complex and highly coordinated cardiac physiological function. Yet the biological and physiological identities and the origin of the specialized cardiomyocyte populations have not been fully comprehended. Here we report a previously unrecognised population of cardiomyocytes expressing Dbhgene encoding dopamine beta-hydroxylase in murine heart. We determined how these myocytes are distributed across the heart by utilising advanced single-cell and spatial transcriptomic analyses, genetic fate mapping and molecular imaging with computational reconstruction. We demonstrated that they form the key functional components of the cardiac conduction system by using optogenetic electrophysiology and conditional cardiomyocyte Dbh gene deletion models. We revealed their close relationship with sympathetic innervation during cardiac conduction system formation. Our study thus provides new insights into the development and heterogeneity of the mammalian cardiac conduction system by revealing a new cardiomyocyte population with potential catecholaminergic endocrine function.
    DOI:  https://doi.org/10.1038/s41467-023-42658-9
  39. Nat Commun. 2023 Dec 02. 14(1): 7954
    Accurate and efficient estimation of local heritability using summary statistics and the linkage disequilibrium matrix.
    Hui Li, Rahul Mazumder, Xihong Lin.
      Existing SNP-heritability estimators that leverage summary statistics from genome-wide association studies (GWAS) are much less efficient (i.e., have larger standard errors) than the restricted maximum likelihood (REML) estimators which require access to individual-level data. We introduce a new method for local heritability estimation-Heritability Estimation with high Efficiency using LD and association Summary Statistics (HEELS)-that significantly improves the statistical efficiency of summary-statistics-based heritability estimator and attains comparable statistical efficiency as REML (with a relative statistical efficiency >92%). Moreover, we propose representing the empirical LD matrix as the sum of a low-rank matrix and a banded matrix. We show that this way of modeling the LD can not only reduce the storage and memory cost, but also improve the computational efficiency of heritability estimation. We demonstrate the statistical efficiency of HEELS and the advantages of our proposed LD approximation strategies both in simulations and through empirical analyses of the UK Biobank data.
    DOI:  https://doi.org/10.1038/s41467-023-43565-9
  40. J Clin Invest. 2023 Dec 01. pii: e175288. [Epub ahead of print]133(23):
    Human brown adipose tissue is not enough to combat cardiometabolic diseases.
    André C Carpentier, Denis P Blondin.
      
    DOI:  https://doi.org/10.1172/JCI175288
  41. Mol Med. 2023 Nov 28. 29(1): 161
    IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling in D-galactose-induced aging mice.
    Xiaohai Zhou, Bowen Tan, Weiwei Gui, Caiping Zhou, Hanxin Zhao, Xihua Lin, Hong Li.
       BACKGROUND: Liver aging, marked by cellular senescence and low-grade inflammation, heightens susceptibility to chronic liver disease and worsens its prognosis. Insulin-like growth factor 2 (IGF2) has been implicated in numerous aging-related diseases. Nevertheless, its role and underlying molecular mechanisms in liver aging remain largely unexplored.
    METHODS: The expression of IGF2 was examined in the liver of young (2-4 months), middle-aged (9-12 months), and old (24-26 months) C57BL/6 mice. In vivo, we used transgenic IGF2f/f; Alb-Cre mice and D-galactose-induced aging model to explore the role of IGF2 in liver aging. In vitro, we used specific short hairpin RNA against IGF2 to knock down IGF2 in AML12 cells. D-galactose and hydrogen peroxide treatment were used to induce AML12 cell senescence.
    RESULTS: We observed a significant reduction of IGF2 levels in the livers of aged mice. Subsequently, we demonstrated that IGF2 deficiency promoted senescence phenotypes and senescence-associated secretory phenotypes (SASPs), both in vitro and in vivo aging models. Moreover, IGF2 deficiency impaired mitochondrial function, reducing mitochondrial respiratory capacity, mitochondrial membrane potential, and nicotinamide adenine dinucleotide (NAD)+/NADH ratio, increasing intracellular and mitochondrial reactive oxygen species levels, and disrupting mitochondrial membrane structure. Additionally, IGF2 deficiency markedly upregulated CCAAT/enhancer-binding protein beta (CEBPB). Notably, inhibiting CEBPB reversed the senescence phenotypes and reduced SASPs induced by IGF2 deficiency.
    CONCLUSIONS: In summary, our findings strongly suggest that IGF2 deficiency promotes liver aging through mitochondrial dysfunction and upregulated CEBPB signaling. These results provide compelling evidence for considering IGF2 as a potential target for interventions aimed at slowing down the process of liver aging.
    Keywords:  Aging; CEBPB; IGF2; Liver; Mitochondria dysfunction
    DOI:  https://doi.org/10.1186/s10020-023-00752-0
  42. EMBO Mol Med. 2023 Nov 27. e18028
    Tumor endothelial cell autophagy is a key vascular-immune checkpoint in melanoma.
    Jelle Verhoeven, Kathryn A Jacobs, Francesca Rizzollo, Francesca Lodi, Yichao Hua, Joanna Poźniak, Adhithya Narayanan Srinivasan, Diede Houbaert, Gautam Shankar, Sanket More, Marco B Schaaf, Nikolina Dubroja Lakic, Maarten Ganne, Jochen Lamote, Johan Van Weyenbergh, Louis Boon, Oliver Bechter, Francesca Bosisio, Yasuo Uchiyama, Mathieu Jm Bertrand, Jean Christophe Marine, Diether Lambrechts, Gabriele Bergers, Madhur Agrawal, Patrizia Agostinis.
      Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T-cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh /AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy, and responders exhibit an increased presence of inflamed vessels interfacing with infiltrating CD8+ T-cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, our study identifies autophagy as a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.
    Keywords:  autophagy; cancer; immunotherapy; inflammation; tumor endothelial cells
    DOI:  https://doi.org/10.15252/emmm.202318028
  43. Nat Commun. 2023 Nov 30. 14(1): 7866
    How carvedilol does not activate β2-adrenoceptors.
    Robert J Lefkowitz, Howard A Rockman, Paul J Shim, Samuel Liu, Seungkirl Ahn, Biswaranjan Pani, Sudarshan Rajagopal, Sudha K Shenoy, Michel Bouvier, Jeffrey L Benovic, Stephen B Liggett, Robert R Ruffolo, Michael R Bristow, Milton Packer.
      
    DOI:  https://doi.org/10.1038/s41467-023-42848-5
  44. Proc Natl Acad Sci U S A. 2023 Dec 05. 120(49): e2302903120
    The USP7-STAT3-granzyme-Par-1 axis regulates allergic inflammation by promoting differentiation of IL-5-producing Th2 cells.
    Jin Kumagai, Masahiro Kiuchi, Kota Kokubo, Hiroyuki Yagyu, Masahiro Nemoto, Kaori Tsuji, Ken Nagahata, Atsushi Sasaki, Takahisa Hishiya, Miki Onoue, Rie Shinmi, Yuri Sonobe, Tomohisa Iinuma, Syuji Yonekura, Jun Shinga, Toyoyuki Hanazawa, Haruhiko Koseki, Toshinori Nakayama, Koutaro Yokote, Kiyoshi Hirahara.
      Uncontrolled type 2 immunity by type 2 helper T (Th2) cells causes intractable allergic diseases; however, whether the interaction of CD4+ T cells shapes the pathophysiology of allergic diseases remains unclear. We identified a subset of Th2 cells that produced the serine proteases granzyme A and B early in differentiation. Granzymes cleave protease-activated receptor (Par)-1 and induce phosphorylation of p38 mitogen-activated protein kinase (MAPK), resulting in the enhanced production of IL-5 and IL-13 in both mouse and human Th2 cells. Ubiquitin-specific protease 7 (USP7) regulates IL-4-induced phosphorylation of STAT3, resulting in granzyme production during Th2 cell differentiation. Genetic deletion of Usp7 or Gzma and pharmacological blockade of granzyme B ameliorated allergic airway inflammation. Furthermore, PAR-1+ and granzyme+ Th2 cells were colocalized in nasal polyps from patients with eosinophilic chronic rhinosinusitis. Thus, the USP7-STAT3-granzymes-Par-1 pathway is a potential therapeutic target for intractable allergic diseases.
    Keywords:  asthma, intractable allergic disease; granzyme; pathogenic Th2 cell; signal transducers and activators of transcription (STAT)3; ubiquitin specific protease 7 (USP7)
    DOI:  https://doi.org/10.1073/pnas.2302903120
  45. Science. 2023 Dec;382(6674): 997-998
    Mutation hotspots during meiosis.
    Frédéric Baudat, Bernard de Massy.
      Multiple pathways generate mutations at sites of meiotic recombination in humans.
    DOI:  https://doi.org/10.1126/science.adl2021
  46. J Clin Invest. 2023 Dec 01. pii: e173715. [Epub ahead of print]133(23):
    High-frequency home self-collection of capillary blood correlates IFI27 expression kinetics with SARS-CoV-2 viral clearance.
    Fang Yun Lim, Soo-Young Kim, Karisma N Kulkarni, Rachel L Blazevic, Louise E Kimball, Hannah G Lea, Amanda J Haack, Maia S Gower, Terry Stevens-Ayers, Lea M Starita, Michael Boeckh, Ollivier Hyrien, Joshua T Schiffer, Ashleigh B Theberge, Alpana Waghmare.
      
    Keywords:  COVID-19; Infectious disease; Innate immunity
    DOI:  https://doi.org/10.1172/JCI173715
  47. Cell Death Dis. 2023 Dec 01. 14(12): 788
    Mitochondrial E3 ligase MARCH5 is a safeguard against DNA-PKcs-mediated immune signaling in mitochondria-damaged cells.
    June Heo, Yeon-Ji Park, Yonghyeon Kim, Ho-Soo Lee, Jeongah Kim, Soon-Hwan Kwon, Myeong-Gyun Kang, Hyun-Woo Rhee, Woong Sun, Jae-Ho Lee, Hyeseong Cho.
      Mitochondrial dysfunction is important in various chronic degenerative disorders, and aberrant immune responses elicited by cytoplasmic mitochondrial DNA (mtDNA) may be related. Here, we developed mtDNA-targeted MTERF1-FokI and TFAM-FokI endonuclease systems to induce mitochondrial DNA double-strand breaks (mtDSBs). In these cells, the mtDNA copy number was significantly reduced upon mtDSB induction. Interestingly, in cGAS knockout cells, synthesis of interferon β1 and interferon-stimulated gene was increased upon mtDSB induction. We found that mtDSBs activated DNA-PKcs and HSPA8 in a VDAC1-dependent manner. Importantly, the mitochondrial E3 ligase MARCH5 bound active DNA-PKcs in cells with mtDSBs and reduced the type І interferon response through the degradation of DNA-PKcs. Likewise, mitochondrial damage caused by LPS treatment in RAW264.7 macrophage cells increased phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA in a DNA-PKcs-dependent manner. Accordingly, in March5 knockout macrophages, phospho-HSPA8 levels and the synthesis of mIFNB1 mRNA were prolonged after LPS stimulation. Together, cytoplasmic mtDNA elicits a cellular immune response through DNA-PKcs, and mitochondrial MARCH5 may be a safeguard to prevent persistent inflammatory reactions.
    DOI:  https://doi.org/10.1038/s41419-023-06315-9
  48. Nat Commun. 2023 Nov 25. 14(1): 7728
    Associations of myeloid cells with cellular and humoral responses following vaccinations in patients with neuroimmunological diseases.
    Meng Wang, Adeline Dehlinger, Camila Fernández Zapata, Maya Golan, Gerardina Gallaccio, Leif E Sander, Stephan Schlickeiser, Desiree Kunkel, Tanja Schmitz-Hübsch, Birgit Sawitzki, Arnon Karni, Julian Braun, Lucie Loyal, Andreas Thiel, Judith Bellmann-Strobl, Friedemann Paul, Lil Meyer-Arndt, Chotima Böttcher.
      Disease-modifying therapies (DMTs) are widely used in neuroimmunological diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Although these treatments are known to predispose patients to infections and affect their responses to vaccination, little is known about the impact of DMTs on the myeloid cell compartment. In this study, we use mass cytometry to examine DMT-associated changes in the innate immune system in untreated and treated patients with MS (n = 39) or NMOSD (n = 23). We also investigated the association between changes in myeloid cell phenotypes and longitudinal responsiveness to homologous primary, secondary, and tertiary SARS-CoV-2 mRNA vaccinations. Multiple DMT-associated myeloid cell clusters, in particular CD64+HLADRlow granulocytes, showed significant correlations with B and T cell responses induced by vaccination. Our findings suggest the potential role of myeloid cells in cellular and humoral responses following vaccination in DMT-treated patients with neuroimmunological diseases.
    DOI:  https://doi.org/10.1038/s41467-023-43553-z
  49. Nat Commun. 2023 Dec 01. 14(1): 7945
    Haplotype-based inference of recent effective population size in modern and ancient DNA samples.
    Romain Fournier, Zoi Tsangalidou, David Reich, Pier Francesco Palamara.
      Individuals sharing recent ancestors are likely to co-inherit large identical-by-descent (IBD) genomic regions. The distribution of these IBD segments in a population may be used to reconstruct past demographic events such as effective population size variation, but accurate IBD detection is difficult in ancient DNA data and in underrepresented populations with limited reference data. In this work, we introduce an accurate method for inferring effective population size variation during the past ~2000 years in both modern and ancient DNA data, called HapNe. HapNe infers recent population size fluctuations using either IBD sharing (HapNe-IBD) or linkage disequilibrium (HapNe-LD), which does not require phasing and can be computed in low coverage data, including data sets with heterogeneous sampling times. HapNe shows improved accuracy in a range of simulated demographic scenarios compared to currently available methods for IBD-based and LD-based inference of recent effective population size, while requiring fewer computational resources. We apply HapNe to several modern populations from the 1,000 Genomes Project, the UK Biobank, the Allen Ancient DNA Resource, and recently published samples from Iron Age Britain, detecting multiple instances of recent effective population size variation across these groups.
    DOI:  https://doi.org/10.1038/s41467-023-43522-6
  50. Nat Commun. 2023 Nov 28. 14(1): 7813
    Adults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01.
    Yunda Huang, Lily Zhang, Shelly Karuna, Philip Andrew, Michal Juraska, Joshua A Weiner, Heather Angier, Evgenii Morgan, Yasmin Azzam, Edith Swann, Srilatha Edupuganti, Nyaradzo M Mgodi, Margaret E Ackerman, Deborah Donnell, Lucio Gama, Peter L Anderson, Richard A Koup, John Hural, Myron S Cohen, Lawrence Corey, M Juliana McElrath, Peter B Gilbert, Maria P Lemos.
      Broadly neutralizing monoclonal antibodies (mAbs) are being developed for HIV-1 prevention. Hence, these mAbs and licensed oral pre-exposure prophylaxis (PrEP) (tenofovir-emtricitabine) can be concomitantly administered in clinical trials. In 48 US participants (men and transgender persons who have sex with men) who received the HIV-1 mAb VRC01 and remained HIV-free in an antibody-mediated-prevention trial (ClinicalTrials.gov #NCT02716675), we conduct a post-hoc analysis and find that VRC01 clearance is 0.08 L/day faster (p = 0.005), and dose-normalized area-under-the-curve of VRC01 serum concentration over-time is 0.29 day/mL lower (p < 0.001) in PrEP users (n = 24) vs. non-PrEP users (n = 24). Consequently, PrEP users are predicted to have 14% lower VRC01 neutralization-mediated prevention efficacy against circulating HIV-1 strains. VRC01 clearance is positively associated (r = 0.33, p = 0.03) with levels of serum intestinal Fatty Acid Binding protein (I-FABP), a marker of epithelial intestinal permeability, which is elevated upon starting PrEP (p = 0.04) and after months of self-reported use (p = 0.001). These findings have implications for the evaluation of future HIV-1 mAbs and postulate a potential mechanism for mAb clearance in the context of PrEP.
    DOI:  https://doi.org/10.1038/s41467-023-43399-5
  51. Aging Cell. 2023 Nov 28. e14040
    Endothelial cell-specific reduction in mTOR ameliorates age-related arterial and metabolic dysfunction.
    Md Torikul Islam, Shelby A Hall, Tavia Dutson, Samuel I Bloom, R Colton Bramwell, John Kim, Jordan R Tucker, Daniel R Machin, Anthony J Donato, Lisa A Lesniewski.
      Systemic inhibition of the mammalian target of rapamycin (mTOR) delays aging and many age-related conditions including arterial and metabolic dysfunction. However, the mechanisms and tissues involved in these beneficial effects remain largely unknown. Here, we demonstrate that activation of S6K, a downstream target of mTOR, is increased in arteries with advancing age, and that this occurs preferentially in the endothelium compared with the vascular smooth muscle. Induced endothelial cell-specific deletion of mTOR reduced protein expression by 60-70%. Although this did not significantly alter arterial and metabolic function in young mice, endothelial mTOR reduction reversed arterial stiffening and improved endothelium-dependent dilation (EDD) in old mice, indicating an improvement in age-related arterial dysfunction. Improvement in arterial function in old mice was concomitant with reductions in arterial cellular senescence, inflammation, and oxidative stress. The reduction in endothelial mTOR also improved glucose tolerance in old mice, and this was associated with attenuated hepatic gluconeogenesis and improved lipid tolerance, but was independent of alterations in peripheral insulin sensitivity, pancreatic beta cell function, or fasted plasma lipids in old mice. Lastly, we found that endothelial mTOR reduction suppressed gene expression of senescence and inflammatory markers in endothelial-rich (i.e., lung) and metabolically active organs (i.e., liver and adipose tissue), which may have contributed to the improvement in metabolic function in old mice. This is the first evidence demonstrating that reducing endothelial mTOR in old age improves arterial and metabolic function. These findings have implications for future drug development.
    Keywords:  aging; arterial stiffness; endothelial cells; inflammation; metabolic function; oxidative stress; senescence; vasodilation
    DOI:  https://doi.org/10.1111/acel.14040
  52. Nat Neurosci. 2023 Dec;26(12): 2048
    Pregnant brains in parent mode.
    Charlotte Arlt.
      
    DOI:  https://doi.org/10.1038/s41593-023-01523-0
  53. Cell. 2023 Nov 18. pii: S0092-8674(23)01217-5. [Epub ahead of print]
    Early cellular mechanisms of type I interferon-driven susceptibility to tuberculosis.
    Dmitri I Kotov, Ophelia V Lee, Stefan A Fattinger, Charlotte A Langner, Jaresley V Guillen, Joshua M Peters, Andres Moon, Eileen M Burd, Kristen C Witt, Daniel B Stetson, David L Jaye, Bryan D Bryson, Russell E Vance.
      Mycobacterium tuberculosis (Mtb) causes 1.6 million deaths annually. Active tuberculosis correlates with a neutrophil-driven type I interferon (IFN) signature, but the cellular mechanisms underlying tuberculosis pathogenesis remain poorly understood. We found that interstitial macrophages (IMs) and plasmacytoid dendritic cells (pDCs) are dominant producers of type I IFN during Mtb infection in mice and non-human primates, and pDCs localize near human Mtb granulomas. Depletion of pDCs reduces Mtb burdens, implicating pDCs in tuberculosis pathogenesis. During IFN-driven disease, we observe abundant DNA-containing neutrophil extracellular traps (NETs) described to activate pDCs. Cell-type-specific disruption of the type I IFN receptor suggests that IFNs act on IMs to inhibit Mtb control. Single-cell RNA sequencing (scRNA-seq) indicates that type I IFN-responsive cells are defective in their response to IFNγ, a cytokine critical for Mtb control. We propose that pDC-derived type I IFNs act on IMs to permit bacterial replication, driving further neutrophil recruitment and active tuberculosis disease.
    Keywords:  Mycobacterium tuberculosis; innate immunology; interstitial macrophages; lung; mice; neutrophil extracellular traps; neutrophils; plasmacytoid dendritic cells; type I interferons
    DOI:  https://doi.org/10.1016/j.cell.2023.11.002
  54. Nat Commun. 2023 Nov 29. 14(1): 7825
    PD-1- CD45RA+ effector-memory CD8 T cells and CXCL10+ macrophages are associated with response to atezolizumab plus bevacizumab in advanced hepatocellular carcinoma.
    Sarah Cappuyns, Gino Philips, Vincent Vandecaveye, Bram Boeckx, Rogier Schepers, Thomas Van Brussel, Ingrid Arijs, Aurelie Mechels, Ayse Bassez, Francesca Lodi, Joris Jaekers, Halit Topal, Baki Topal, Orian Bricard, Junbin Qian, Eric Van Cutsem, Chris Verslype, Diether Lambrechts, Jeroen Dekervel.
      The combination of atezolizumab plus bevacizumab (atezo/bev) has dramatically changed the treatment landscape of advanced HCC (aHCC), achieving durable responses in some patients. Using single-cell transcriptomics, we characterize the intra-tumoural and peripheral immune context of patients with aHCC treated with atezo/bev. Tumours from patients with durable responses are enriched for PDL1+ CXCL10+ macrophages and, based on cell-cell interaction analysis, express high levels of CXCL9/10/11 and are predicted to attract peripheral CXCR3+ CD8+ effector-memory T cells (CD8 TEM) into the tumour. Based on T cell receptor sharing and pseudotime trajectory analysis, we propose that CD8 TEM preferentially differentiate into clonally-expanded PD1- CD45RA+ effector-memory CD8+ T cells (CD8 TEMRA) with pronounced cytotoxicity. In contrast, in non-responders, CD8 TEM remain frozen in their effector-memory state. Finally, in responders, CD8 TEMRA display a high degree of T cell receptor sharing with blood, consistent with their patrolling activity. These findings may help understand the possible mechanisms underlying response to atezo/bev in aHCC.
    DOI:  https://doi.org/10.1038/s41467-023-43381-1
  55. Sci Immunol. 2023 Dec;8(90): eadl1470
    The chilling origin of germinal centers.
    Thomas Boehm.
      Germinal center-like structures have been identified in ectothermic vertebrates, establishing germinal centers as a universal component of humoral immunity (see related Research Article by Shibasaki et al.).
    DOI:  https://doi.org/10.1126/sciimmunol.adl1470
  56. Nature. 2023 Nov 29.
    FOXP3 recognizes microsatellites and bridges DNA through multimerization.
    Wenxiang Zhang, Fangwei Leng, Xi Wang, Ricardo N Ramirez, Jinseok Park, Christophe Benoist, Sun Hur.
      FOXP3 is a transcription factor that is essential for the development of regulatory T cells, a branch of T cells that suppress excessive inflammation and autoimmunity1-5. However, the molecular mechanisms of FOXP3 remain unclear. Here we here show that FOXP3 uses the forkhead domain-a DNA-binding domain that is commonly thought to function as a monomer or dimer-to form a higher-order multimer after binding to TnG repeat microsatellites. The cryo-electron microscopy structure of FOXP3 in a complex with T3G repeats reveals a ladder-like architecture, whereby two double-stranded DNA molecules form the two 'side rails' bridged by five pairs of FOXP3 molecules, with each pair forming a 'rung'. Each FOXP3 subunit occupies TGTTTGT within the repeats in a manner that is indistinguishable from that of FOXP3 bound to the forkhead consensus motif (TGTTTAC). Mutations in the intra-rung interface impair TnG repeat recognition, DNA bridging and the cellular functions of FOXP3, all without affecting binding to the forkhead consensus motif. FOXP3 can tolerate variable inter-rung spacings, explaining its broad specificity for TnG-repeat-like sequences in vivo and in vitro. Both FOXP3 orthologues and paralogues show similar TnG repeat recognition and DNA bridging. These findings therefore reveal a mode of DNA recognition that involves transcription factor homomultimerization and DNA bridging, and further implicates microsatellites in transcriptional regulation and diseases.
    DOI:  https://doi.org/10.1038/s41586-023-06793-z
  57. Sci Adv. 2023 Dec;9(48): eadg8014
    Harnessing T cell exhaustion and trogocytosis to isolate patient-derived tumor-specific TCR.
    Francesco Manfredi, Lorena Stasi, Silvia Buonanno, Francesca Marzuttini, Maddalena Noviello, Sara Mastaglio, Danilo Abbati, Alessia Potenza, Chiara Balestrieri, Beatrice Claudia Cianciotti, Elena Tassi, Sara Feola, Cristina Toffalori, Marco Punta, Zulma Magnani, Barbara Camisa, Elena Tiziano, Maria Teresa Lupo-Stanghellini, Rui Mamede Branca, Janne Lehtiö, Tiina M Sikanen, Markus J Haapala, Vincenzo Cerullo, Monica Casucci, Luca Vago, Fabio Ciceri, Chiara Bonini, Eliana Ruggiero.
      To study and then harness the tumor-specific T cell dynamics after allogeneic hematopoietic stem cell transplant, we typed the frequency, phenotype, and function of lymphocytes directed against tumor-associated antigens (TAAs) in 39 consecutive transplanted patients, for 1 year after transplant. We showed that TAA-specific T cells circulated in 90% of patients but display a limited effector function associated to an exhaustion phenotype, particularly in the subgroup of patients deemed to relapse, where exhausted stem cell memory T cells accumulated. Accordingly, cancer-specific cytolytic functions were relevant only when the TAA-specific T cell receptors (TCRs) were transferred into healthy, genome-edited T cells. We then exploited trogocytosis and ligandome-on-chip technology to unveil the specificities of tumor-specific TCRs retrieved from the exhausted T cell pool. Overall, we showed that harnessing circulating TAA-specific and exhausted T cells allow to isolate TCRs against TAAs and previously not described acute myeloid leukemia antigens, potentially relevant for T cell-based cancer immunotherapy.
    DOI:  https://doi.org/10.1126/sciadv.adg8014
  58. Nat Commun. 2023 Nov 30. 14(1): 7902
    CurveCurator: a recalibrated F-statistic to assess, classify, and explore significance of dose-response curves.
    Florian P Bayer, Manuel Gander, Bernhard Kuster, Matthew The.
      Dose-response curves are key metrics in pharmacology and biology to assess phenotypic or molecular actions of bioactive compounds in a quantitative fashion. Yet, it is often unclear whether or not a measured response significantly differs from a curve without regulation, particularly in high-throughput applications or unstable assays. Treating potency and effect size estimates from random and true curves with the same level of confidence can lead to incorrect hypotheses and issues in training machine learning models. Here, we present CurveCurator, an open-source software that provides reliable dose-response characteristics by computing p-values and false discovery rates based on a recalibrated F-statistic and a target-decoy procedure that considers dataset-specific effect size distributions. The application of CurveCurator to three large-scale datasets enables a systematic drug mode of action analysis and demonstrates its scalable utility across several application areas, facilitated by a performant, interactive dashboard for fast data exploration.
    DOI:  https://doi.org/10.1038/s41467-023-43696-z
  59. Sci Immunol. 2023 Dec;8(90): eadf4919
    Noncanonical MAVS signaling restrains dendritic cell-driven antitumor immunity by inhibiting IL-12.
    Lingling Wu, Xiaochuan Hong, Chao Yang, Yuanqin Yang, Wenwen Li, Lu Lu, Meichun Cai, Dongqing Cao, Guanglei Zhuang, Liufu Deng.
      Mitochondrial antiviral signaling protein (MAVS)-mediated cytosolic RNA sensing plays a central role in tumor immunogenicity. However, the effects of host MAVS signaling on antitumor immunity remain unclear. Here, we demonstrate that the host MAVS pathway supports tumor growth and impairs antitumor immunity, whereas MAVS deficiency in dendritic cells (DCs) promotes tumor-reactive CD8+ T cell responses. Specifically, CD8+ T cell priming capacity was enhanced by MAVS ablation in a type I interferon-independent, but IL-12-dependent, manner. Mechanistically, loss of the RIG-I/MAVS cascade activated the noncanonical NF-κB pathway and in turn induced IL-12 production by DCs. MAVS-restrained IL-12 promoted cross-talk between CD8+ T cells and DCs, which was licensed by IFN-γ. Moreover, ablation of host MAVS sensitized tumors to immunotherapy and attenuated radiation resistance, thereby facilitating the maintenance of effector CD8+ T cells. These findings demonstrate that the host MAVS pathway acts as an immune regulator of DC-driven antitumor immunity and support the development of immunotherapies that antagonize MAVS signaling in DCs.
    DOI:  https://doi.org/10.1126/sciimmunol.adf4919
  60. Nat Neurosci. 2023 Dec;26(12): 2048
    Myelin and Alzheimer's disease.
    Rebecca Wright.
      
    DOI:  https://doi.org/10.1038/s41593-023-01524-z
  61. Nat Commun. 2023 Dec 01. 14(1): 7922
    Intrinsic factors and CD1d1 but not CD1d2 expression levels control invariant natural killer T cell subset differentiation.
    Ludivine Amable, Luis Antonio Ferreira Martins, Remi Pierre, Marcio Do Cruseiro, Ghita Chabab, Arnauld Sergé, Camille Kergaravat, Marc Delord, Christophe Viret, Jean Jaubert, Chaohong Liu, Saoussen Karray, Julien C Marie, Magali Irla, Hristo Georgiev, Emmanuel Clave, Antoine Toubert, Bruno Lucas, Jihene Klibi, Kamel Benlagha.
      Invariant natural killer T (NKT) cell subsets are defined based on their cytokine-production profiles and transcription factors. Their distribution is different in C57BL/6 (B6) and BALB/c mice, with a bias for NKT1 and NKT2/NKT17 subsets, respectively. Here, we show that the non-classical class I-like major histocompatibility complex CD1 molecules CD1d2, expressed in BALB/c and not in B6 mice, could not account for this difference. We find however that NKT cell subset distribution is intrinsic to bone marrow derived NKT cells, regardless of syngeneic CD1d-ligand recognition, and that multiple intrinsic factors are likely involved. Finally, we find that CD1d expression levels in combination with T cell antigen receptor signal strength could also influence NKT cell distribution and function. Overall, this study indicates that CD1d-mediated TCR signals and other intrinsic signals integrate to influence strain-specific NKT cell differentiation programs and subset distributions.
    DOI:  https://doi.org/10.1038/s41467-023-43424-7
  62. Nat Neurosci. 2023 Nov 27.
    Whole-brain in vivo base editing reverses behavioral changes in Mef2c-mutant mice.
    Wei-Ke Li, Shu-Qian Zhang, Wan-Ling Peng, Yu-Han Shi, Bo Yuan, Yi-Ting Yuan, Zhen-Yu Xue, Jin-Cheng Wang, Wen-Jian Han, Zhi-Fang Chen, Shi-Fang Shan, Bi-Qing Xue, Jin-Long Chen, Cheng Zhang, Shu-Jia Zhu, Yi-Lin Tai, Tian-Lin Cheng, Zi-Long Qiu.
      Whole-brain genome editing to correct single-base mutations and reduce or reverse behavioral changes in animal models of autism spectrum disorder (ASD) has not yet been achieved. We developed an apolipoprotein B messenger RNA-editing enzyme, catalytic polypeptide-embedded cytosine base editor (AeCBE) system for converting C·G to T·A base pairs. We demonstrate its effectiveness by targeting AeCBE to an ASD-associated mutation of the MEF2C gene (c.104T>C, p.L35P) in vivo in mice. We first constructed Mef2cL35P heterozygous mice. Male heterozygous mice exhibited hyperactivity, repetitive behavior and social abnormalities. We then programmed AeCBE to edit the mutated C·G base pairs of Mef2c in the mouse brain through the intravenous injection of blood-brain barrier-crossing adeno-associated virus. This treatment successfully restored Mef2c protein levels in several brain regions and reversed the behavioral abnormalities in Mef2c-mutant mice. Our work presents an in vivo base-editing paradigm that could potentially correct single-base genetic mutations in the brain.
    DOI:  https://doi.org/10.1038/s41593-023-01499-x
  63. Nat Metab. 2023 Nov 27.
    Efferocytosis-induced lactate enables the proliferation of pro-resolving macrophages to mediate tissue repair.
    David Ngai, Maaike Schilperoort, Ira Tabas.
      The clearance of apoptotic cells by macrophages (efferocytosis) prevents necrosis and inflammation and activates pro-resolving pathways, including continual efferocytosis. A key resolution process in vivo is efferocytosis-induced macrophage proliferation (EIMP), in which apoptotic cell-derived nucleotides trigger Myc-mediated proliferation of pro-resolving macrophages. Here we show that EIMP requires a second input that is integrated with cellular metabolism, notably efferocytosis-induced lactate production. Lactate signalling via GPR132 promotes Myc protein stabilization and subsequent macrophage proliferation. This mechanism is validated in vivo using a mouse model of dexamethasone-induced thymocyte apoptosis, which elevates apoptotic cell burden and requires efferocytosis to prevent inflammation and necrosis. Thus, EIMP, a key process in tissue resolution, requires inputs from two independent processes: a signalling pathway induced by apoptotic cell-derived nucleotides and a cellular metabolism pathway involving lactate production. These findings illustrate how seemingly distinct pathways in efferocytosing macrophages are integrated to carry out a key process in tissue resolution.
    DOI:  https://doi.org/10.1038/s42255-023-00921-9
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