bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–10–01
forty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The extraterrestrial search for our own chemical origins.
  2. Human microglial state dynamics in Alzheimer's disease progression.
  3. Finding a different path.
  4. TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
  5. APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints.
  6. An epigenetic clock in plants.
  7. IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice.
  8. FEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins.
  9. How mothers program sons to use their Y chromosomes.
  10. Early Alzheimer's disease pathology in human cortex involves transient cell states.
  11. Senolytic therapy for Alzheimer's disease.
  12. Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets.
  13. A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils.
  14. Spatial atlas of the mouse central nervous system at molecular resolution.
  15. Linking non-coding variants to function in microglia in Alzheimer's disease.
  16. Myo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset.
  17. Global mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions.
  18. Tracing immune cells around biomaterials with spatial anchors during large-scale wound regeneration.
  19. Multi-omics profiling reveals rhythmic liver function shaped by meal timing.
  20. Proteome census upon nutrient stress reveals Golgiphagy membrane receptors.
  21. The leaderless communication peptide (LCP) class of quorum-sensing peptides is broadly distributed among Firmicutes.
  22. Functional screening and rational design of compounds targeting GPR132 to treat diabetes.
  23. The brain cells linked to protection against dementia.
  24. All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.
  25. Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration.
  26. On the visual analytic intelligence of neural networks.
  27. Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson's disease.
  28. The AD odyssey 2023: Tales of single cell.
  29. Myeloid BAF60a deficiency alters metabolic homeostasis and exacerbates atherosclerosis.
  30. Co-designing to enable modern aging.
  31. Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
  32. A Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils.
  33. Single-cell epigenome analysis identifies molecular events controlling direct conversion of human fibroblasts to pancreatic ductal-like cells.
  34. NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis.
  35. Epigenomic dissection of Alzheimer's disease pinpoints causal variants and reveals epigenome erosion.
  36. Multitissue H3K27ac profiling of GTEx samples links epigenomic variation to disease.
  37. How Dolly the sheep's legacy lives on: CRISPR cattle and cloned camels.
  38. GiRAFR improves gRNA detection and annotation in single-cell CRISPR screens.
  39. The very first beat: how a heart starts to pulse.
  40. An evolutionary epigenetic clock in plants.
  41. Epitranscriptomic subtyping, visualization, and denoising by global motif visualization.
  42. γδ T cell explorations seek terra firma.
  43. Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.
  44. Suppression of protein quality control system by TRIM30a sensitises tumour cells to NK cell-mediated immune surveillance.
  45. Engineering microbial division of labor for plastic upcycling.
  46. Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology.
  1. Nat Commun. 2023 Sep 25. 14(1): 5794
    The extraterrestrial search for our own chemical origins.
      
    DOI:  https://doi.org/10.1038/s41467-023-41009-y
  2. Cell. 2023 Sep 28. pii: S0092-8674(23)00971-6. [Epub ahead of print]186(20): 4386-4403.e29
    Human microglial state dynamics in Alzheimer's disease progression.
    Na Sun, Matheus B Victor, Yongjin P Park, Xushen Xiong, Aine Ni Scannail, Noelle Leary, Shaniah Prosper, Soujanya Viswanathan, Xochitl Luna, Carles A Boix, Benjamin T James, Yosuke Tanigawa, Kyriaki Galani, Hansruedi Mathys, Xueqiao Jiang, Ayesha P Ng, David A Bennett, Li-Huei Tsai, Manolis Kellis.
      Altered microglial states affect neuroinflammation, neurodegeneration, and disease but remain poorly understood. Here, we report 194,000 single-nucleus microglial transcriptomes and epigenomes across 443 human subjects and diverse Alzheimer's disease (AD) pathological phenotypes. We annotate 12 microglial transcriptional states, including AD-dysregulated homeostatic, inflammatory, and lipid-processing states. We identify 1,542 AD-differentially-expressed genes, including both microglia-state-specific and disease-stage-specific alterations. By integrating epigenomic, transcriptomic, and motif information, we infer upstream regulators of microglial cell states, gene-regulatory networks, enhancer-gene links, and transcription-factor-driven microglial state transitions. We demonstrate that ectopic expression of our predicted homeostatic-state activators induces homeostatic features in human iPSC-derived microglia-like cells, while inhibiting activators of inflammation can block inflammatory progression. Lastly, we pinpoint the expression of AD-risk genes in microglial states and differential expression of AD-risk genes and their regulators during AD progression. Overall, we provide insights underlying microglial states, including state-specific and AD-stage-specific microglial alterations at unprecedented resolution.
    Keywords:  Alzheimer's; cell states; disease-stage response; iPSCs; inflammation; microglia; single-cell; transcription factors
    DOI:  https://doi.org/10.1016/j.cell.2023.08.037
  3. Science. 2023 Sep 29. 381(6665): 1490
    Finding a different path.
    Georgios Louloudis.
      
    DOI:  https://doi.org/10.1126/science.adl0032
  4. Nat Commun. 2023 Sep 29. 14(1): 6099
    TMEM135 links peroxisomes to the regulation of brown fat mitochondrial fission and energy homeostasis.
    Donghua Hu, Min Tan, Dongliang Lu, Brian Kleiboeker, Xuejing Liu, Hongsuk Park, Alexxai V Kravitz, Kooresh I Shoghi, Yu-Hua Tseng, Babak Razani, Akihiro Ikeda, Irfan J Lodhi.
      Mitochondrial morphology, which is controlled by mitochondrial fission and fusion, is an important regulator of the thermogenic capacity of brown adipocytes. Adipose-specific peroxisome deficiency impairs thermogenesis by inhibiting cold-induced mitochondrial fission due to decreased mitochondrial membrane content of the peroxisome-derived lipids called plasmalogens. Here, we identify TMEM135 as a critical mediator of the peroxisomal regulation of mitochondrial fission and thermogenesis. Adipose-specific TMEM135 knockout in mice blocks mitochondrial fission, impairs thermogenesis, and increases diet-induced obesity and insulin resistance. Conversely, TMEM135 overexpression promotes mitochondrial division, counteracts obesity and insulin resistance, and rescues thermogenesis in peroxisome-deficient mice. Mechanistically, thermogenic stimuli promote association between peroxisomes and mitochondria and plasmalogen-dependent localization of TMEM135 in mitochondria, where it mediates PKA-dependent phosphorylation and mitochondrial retention of the fission factor Drp1. Together, these results reveal a previously unrecognized inter-organelle communication regulating mitochondrial fission and energy homeostasis and identify TMEM135 as a potential target for therapeutic activation of BAT.
    DOI:  https://doi.org/10.1038/s41467-023-41849-8
  5. Nat Immunol. 2023 Sep 25.
    APOE4 impairs the microglial response in Alzheimer's disease by inducing TGFβ-mediated checkpoints.
    Zhuoran Yin, Neta Rosenzweig, Kilian L Kleemann, Xiaoming Zhang, Wesley Brandão, Milica A Margeta, Caitlin Schroeder, Kisha N Sivanathan, Sebastian Silveira, Christian Gauthier, Dania Mallah, Kristen M Pitts, Ana Durao, Shawn Herron, Hannah Shorey, Yiran Cheng, Jen-Li Barry, Rajesh K Krishnan, Sam Wakelin, Jared Rhee, Anthony Yung, Michael Aronchik, Chao Wang, Nimansha Jain, Xin Bao, Emma Gerrits, Nieske Brouwer, Amy Deik, Daniel G Tenen, Tsuneya Ikezu, Nicolas G Santander, Gabriel L McKinsey, Caroline Baufeld, Dean Sheppard, Susanne Krasemann, Roni Nowarski, Bart J L Eggen, Clary Clish, Rudolph E Tanzi, Charlotte Madore, Thomas D Arnold, David M Holtzman, Oleg Butovsky.
      The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD). The contribution of microglial APOE4 to AD pathogenesis is unknown, although APOE has the most enriched gene expression in neurodegenerative microglia (MGnD). Here, we show in mice and humans a negative role of microglial APOE4 in the induction of the MGnD response to neurodegeneration. Deletion of microglial APOE4 restores the MGnD phenotype associated with neuroprotection in P301S tau transgenic mice and decreases pathology in APP/PS1 mice. MGnD-astrocyte cross-talk associated with β-amyloid (Aβ) plaque encapsulation and clearance are mediated via LGALS3 signaling following microglial APOE4 deletion. In the brains of AD donors carrying the APOE4 allele, we found a sex-dependent reciprocal induction of AD risk factors associated with suppression of MGnD genes in females, including LGALS3, compared to individuals homozygous for the APOE3 allele. Mechanistically, APOE4-mediated induction of ITGB8-transforming growth factor-β (TGFβ) signaling impairs the MGnD response via upregulation of microglial homeostatic checkpoints, including Inpp5d, in mice. Deletion of Inpp5d in microglia restores MGnD-astrocyte cross-talk and facilitates plaque clearance in APP/PS1 mice. We identify the microglial APOE4-ITGB8-TGFβ pathway as a negative regulator of microglial response to AD pathology, and restoring the MGnD phenotype via blocking ITGB8-TGFβ signaling provides a promising therapeutic intervention for AD.
    DOI:  https://doi.org/10.1038/s41590-023-01627-6
  6. Science. 2023 Sep 29. 381(6665): 1416
    An epigenetic clock in plants.
    P R V Satyaki.
      DNA methylation can identify evolutionary relationships among close plant lineages.
    DOI:  https://doi.org/10.1126/science.adk2696
  7. Nat Neurosci. 2023 Sep 25.
    IL-12 sensing in neurons induces neuroprotective CNS tissue adaptation and attenuates neuroinflammation in mice.
    Myrto Andreadou, Florian Ingelfinger, Donatella De Feo, Teresa L M Cramer, Selma Tuzlak, Ekaterina Friebel, Bettina Schreiner, Pascale Eede, Shirin Schneeberger, Maria Geesdorf, Frederike Ridder, Christina A Welsh, Laura Power, Daniel Kirschenbaum, Shiva K Tyagarajan, Melanie Greter, Frank L Heppner, Sarah Mundt, Burkhard Becher.
      Interleukin-12 (IL-12) is a potent driver of type 1 immunity. Paradoxically, in autoimmune conditions, including of the CNS, IL-12 reduces inflammation. The underlying mechanism behind these opposing properties and the involved cellular players remain elusive. Here we map IL-12 receptor (IL-12R) expression to NK and T cells as well as neurons and oligodendrocytes. Conditionally ablating the IL-12R across these cell types in adult mice and assessing their susceptibility to experimental autoimmune encephalomyelitis revealed that the neuroprotective role of IL-12 is mediated by neuroectoderm-derived cells, specifically neurons, and not immune cells. In human brain tissue from donors with multiple sclerosis, we observe an IL-12R distribution comparable to mice, suggesting similar mechanisms in mice and humans. Combining flow cytometry, bulk and single-nucleus RNA sequencing, we reveal an IL-12-induced neuroprotective tissue adaption preventing early neurodegeneration and sustaining trophic factor release during neuroinflammation, thereby maintaining CNS integrity in mice.
    DOI:  https://doi.org/10.1038/s41593-023-01435-z
  8. Nat Commun. 2023 Sep 27. 14(1): 6015
    FEAST: A flow cytometry-based toolkit for interrogating microglial engulfment of synaptic and myelin proteins.
    Lasse Dissing-Olesen, Alec J Walker, Qian Feng, Helena J Barr, Alicia C Walker, Lili Xie, Daniel K Wilton, Indrani Das, Larry I Benowitz, Beth Stevens.
      Although engulfment is a hallmark of microglia function, fully validated platforms that facilitate high-throughput quantification of this process are lacking. Here, we present FEAST (Flow cytometric Engulfment Assay for Specific Target proteins), which enables interrogation of in vivo engulfment of synaptic material by brain resident macrophages at single-cell resolution. We optimize FEAST for two different analyses: quantification of fluorescent material inside live cells and of engulfed endogenous proteins within fixed cells. To overcome false-positive engulfment signals, we introduce an approach suitable for interrogating engulfment in microglia from perfusion-fixed tissue. As a proof-of-concept for the specificity and versatility of FEAST, we examine the engulfment of synaptic proteins after optic nerve crush and of myelin in two mouse models of demyelination (treatment with cuprizone and injections of lysolecithin). We find that microglia, but not brain-border associated macrophages, engulf in these contexts. Our work underscores how FEAST can be utilized to gain critical insight into functional neuro-immune interactions that shape development, homeostasis, and disease.
    DOI:  https://doi.org/10.1038/s41467-023-41448-7
  9. Nat Cell Biol. 2023 Sep 25.
    How mothers program sons to use their Y chromosomes.
      
    DOI:  https://doi.org/10.1038/s41556-023-01239-0
  10. Cell. 2023 Sep 28. pii: S0092-8674(23)00859-0. [Epub ahead of print]186(20): 4438-4453.e23
    Early Alzheimer's disease pathology in human cortex involves transient cell states.
    Vahid Gazestani, Tushar Kamath, Naeem M Nadaf, Antonios Dougalis, S J Burris, Brendan Rooney, Antti Junkkari, Charles Vanderburg, Anssi Pelkonen, Mireia Gomez-Budia, Nelli-Noora Välimäki, Tuomas Rauramaa, Martine Therrien, Anne M Koivisto, Matthew Tegtmeyer, Sanna-Kaisa Herukka, Abdulraouf Abdulraouf, Samuel E Marsh, Mikko Hiltunen, Ralda Nehme, Tarja Malm, Beth Stevens, Ville Leinonen, Evan Z Macosko.
      Cellular perturbations underlying Alzheimer's disease (AD) are primarily studied in human postmortem samples and model organisms. Here, we generated a single-nucleus atlas from a rare cohort of cortical biopsies from living individuals with varying degrees of AD pathology. We next performed a systematic cross-disease and cross-species integrative analysis to identify a set of cell states that are specific to early AD pathology. These changes-which we refer to as the early cortical amyloid response-were prominent in neurons, wherein we identified a transitional hyperactive state preceding the loss of excitatory neurons, which we confirmed by acute slice physiology on independent biopsy specimens. Microglia overexpressing neuroinflammatory-related processes also expanded as AD pathology increased. Finally, both oligodendrocytes and pyramidal neurons upregulated genes associated with β-amyloid production and processing during this early hyperactive phase. Our integrative analysis provides an organizing framework for targeting circuit dysfunction, neuroinflammation, and amyloid production early in AD pathogenesis.
    Keywords:  Alzheimer’s disease; amyloid pathology; disease systems biology; human cortex; meta-analysis; microglia disease response; neuronal hyperactivity; single-nucleus RNA sequencing; β-amyloid metabolism
    DOI:  https://doi.org/10.1016/j.cell.2023.08.005
  11. Nat Med. 2023 Sep 27.
    Senolytic therapy for Alzheimer's disease.
    Frank M Longo, Stephen M Massa.
      
    DOI:  https://doi.org/10.1038/s41591-023-02541-y
  12. Nat Commun. 2023 Sep 27. 14(1): 6030
    Proteomic and genetic analyses of influenza A viruses identify pan-viral host targets.
    Kelsey M Haas, Michael J McGregor, Mehdi Bouhaddou, Benjamin J Polacco, Eun-Young Kim, Thong T Nguyen, Billy W Newton, Matthew Urbanowski, Heejin Kim, Michael A P Williams, Veronica V Rezelj, Alexandra Hardy, Andrea Fossati, Erica J Stevenson, Ellie Sukerman, Tiffany Kim, Sudhir Penugonda, Elena Moreno, Hannes Braberg, Yuan Zhou, Giorgi Metreveli, Bhavya Harjai, Tia A Tummino, James E Melnyk, Margaret Soucheray, Jyoti Batra, Lars Pache, Laura Martin-Sancho, Jared Carlson-Stevermer, Alexander S Jureka, Christopher F Basler, Kevan M Shokat, Brian K Shoichet, Leah P Shriver, Jeffrey R Johnson, Megan L Shaw, Sumit K Chanda, Dan M Roden, Tonia C Carter, Leah C Kottyan, Rex L Chisholm, Jennifer A Pacheco, Maureen E Smith, Steven J Schrodi, Randy A Albrecht, Marco Vignuzzi, Lorena Zuliani-Alvarez, Danielle L Swaney, Manon Eckhardt, Steven M Wolinsky, Kris M White, Judd F Hultquist, Robyn M Kaake, Adolfo García-Sastre, Nevan J Krogan.
      Influenza A Virus (IAV) is a recurring respiratory virus with limited availability of antiviral therapies. Understanding host proteins essential for IAV infection can identify targets for alternative host-directed therapies (HDTs). Using affinity purification-mass spectrometry and global phosphoproteomic and protein abundance analyses using three IAV strains (pH1N1, H3N2, H5N1) in three human cell types (A549, NHBE, THP-1), we map 332 IAV-human protein-protein interactions and identify 13 IAV-modulated kinases. Whole exome sequencing of patients who experienced severe influenza reveals several genes, including scaffold protein AHNAK, with predicted loss-of-function variants that are also identified in our proteomic analyses. Of our identified host factors, 54 significantly alter IAV infection upon siRNA knockdown, and two factors, AHNAK and coatomer subunit COPB1, are also essential for productive infection by SARS-CoV-2. Finally, 16 compounds targeting our identified host factors suppress IAV replication, with two targeting CDK2 and FLT3 showing pan-antiviral activity across influenza and coronavirus families. This study provides a comprehensive network model of IAV infection in human cells, identifying functional host targets for pan-viral HDT.
    DOI:  https://doi.org/10.1038/s41467-023-41442-z
  13. Nat Commun. 2023 09 23. 14(1): 5949
    A subset of type-II collagen-binding antibodies prevents experimental arthritis by inhibiting FCGR3 signaling in neutrophils.
    Zhongwei Xu, Bingze Xu, Susanna L Lundström, Àlex Moreno-Giró, Danxia Zhao, Myriam Martin, Erik Lönnblom, Qixing Li, Alexander Krämer, Changrong Ge, Lei Cheng, Bibo Liang, Dongmei Tong, Roma Stawikowska, Anna M Blom, Gregg B Fields, Roman A Zubarev, Rikard Holmdahl.
      Rheumatoid arthritis (RA) involves several classes of pathogenic autoantibodies, some of which react with type-II collagen (COL2) in articular cartilage. We previously described a subset of COL2 antibodies targeting the F4 epitope (ERGLKGHRGFT) that could be regulatory. Here, using phage display, we developed recombinant antibodies against this epitope and examined the underlying mechanism of action. One of these antibodies, R69-4, protected against cartilage antibody- and collagen-induced arthritis in mice, but not autoimmune disease models independent of arthritogenic autoantibodies. R69-4 was further shown to cross-react with a large range of proteins within the inflamed synovial fluid, such as the complement protein C1q. Complexed R69-4 inhibited neutrophil FCGR3 signaling, thereby impairing downstream IL-1β secretion and neutrophil self-orchestrated recruitment. Likewise, human isotypes of R69-4 protected against arthritis with comparable efficiency. We conclude that R69-4 abrogates autoantibody-mediated arthritis mainly by hindering FCGR3 signaling, highlighting its potential clinical utility in acute RA.
    DOI:  https://doi.org/10.1038/s41467-023-41561-7
  14. Nature. 2023 Sep 27.
    Spatial atlas of the mouse central nervous system at molecular resolution.
    Hailing Shi, Yichun He, Yiming Zhou, Jiahao Huang, Kamal Maher, Brandon Wang, Zefang Tang, Shuchen Luo, Peng Tan, Morgan Wu, Zuwan Lin, Jingyi Ren, Yaman Thapa, Xin Tang, Ken Y Chan, Benjamin E Deverman, Hao Shen, Albert Liu, Jia Liu, Xiao Wang.
      Spatially charting molecular cell types at single-cell resolution across the 3D volume is critical for illustrating the molecular basis of brain anatomy and functions. Single-cell RNA sequencing has profiled molecular cell types in the mouse brain1,2, but cannot capture their spatial organization. Here we used an in situ sequencing method, STARmap PLUS3,4, to profile 1,022 genes in 3D at a voxel size of 194 × 194 × 345 nm3, mapping 1.09 million high-quality cells across the adult mouse brain and spinal cord. We developed computational pipelines to segment, cluster and annotate 230 molecular cell types by single-cell gene expression and 106 molecular tissue regions by spatial niche gene expression. Joint analysis of molecular cell types and molecular tissue regions enabled a systematic molecular spatial cell-type nomenclature and identification of tissue architectures that were undefined in established brain anatomy. To create a transcriptome-wide spatial atlas, we integrated STARmap PLUS measurements with a published single-cell RNA-sequencing atlas1, imputing single-cell expression profiles of 11,844 genes. Finally, we delineated viral tropisms of a brain-wide transgene delivery tool, AAV-PHP.eB5,6. Together, this annotated dataset provides a single-cell resource that integrates the molecular spatial atlas, brain anatomy and the accessibility to genetic manipulation of the mammalian central nervous system.
    DOI:  https://doi.org/10.1038/s41586-023-06569-5
  15. Nat Genet. 2023 Sep 25.
    Linking non-coding variants to function in microglia in Alzheimer's disease.
      
    DOI:  https://doi.org/10.1038/s41588-023-01503-x
  16. Nat Commun. 2023 09 25. 14(1): 5977
    Myo9b mutations are associated with altered dendritic cell functions and increased susceptibility to autoimmune diabetes onset.
    Jing Zhang, Yuan Zou, Longmin Chen, Fei Sun, Qianqian Xu, Qing Zhou, Yi Wang, Xi Luo, Na Wang, Yang Li, Shu Zhang, Fei Xiong, Ping Yang, Shiwei Liu, Tao Yang, Jianping Weng, Décio L Eizirik, Jinhua Yan, Zhiguang Zhou, Cong-Yi Wang.
      The regulation of autoimmunity against pancreatic islet β cells for type 1 diabetes (T1D) onset is still unclear. NOD/ShiLtJ (NOD) mice are prone to the onset of autoimmune diabetes, but its congenic strain, ALR/Lt (ALR), is not. Here we show that dendritic cells (DC) in ALR mice have impaired migratory and T-cell priming capability. Genomic comparative analysis maps a 33-bp deletion in the ALR Myosin IXb (Myo9b) gene when compared with NOD genome; meanwhile, data from knock-in models show that this ALR Myo9b allele impairs phenotypic and functional maturation of DCs, and prevents the development and progression of spontaneous autoimmune diabetes in NOD mice. In parallel, while the ALR 33-bp deletion of Myo9b is not conserved in human, we find a MYO9B R133Q polymorphism associating with increased risk of T1D and enhanced DC function in patients with T1D. Our results thus hint that alterations in Myo9b may contribute to altered DC function and autoimmune diabetes onset.
    DOI:  https://doi.org/10.1038/s41467-023-41534-w
  17. Nat Commun. 2023 Sep 28. 14(1): 6073
    Global mapping of RNA-chromatin contacts reveals a proximity-dominated connectivity model for ncRNA-gene interactions.
    Charles Limouse, Owen K Smith, David Jukam, Kelsey A Fryer, William J Greenleaf, Aaron F Straight.
      Non-coding RNAs (ncRNAs) are transcribed throughout the genome and provide regulatory inputs to gene expression through their interaction with chromatin. Yet, the genomic targets and functions of most ncRNAs are unknown. Here we use chromatin-associated RNA sequencing (ChAR-seq) to map the global network of ncRNA interactions with chromatin in human embryonic stem cells and the dynamic changes in interactions during differentiation into definitive endoderm. We uncover general principles governing the organization of the RNA-chromatin interactome, demonstrating that nearly all ncRNAs exclusively interact with genes in close three-dimensional proximity to their locus and provide a model predicting the interactome. We uncover RNAs that interact with many loci across the genome and unveil thousands of unannotated RNAs that dynamically interact with chromatin. By relating the dynamics of the interactome to changes in gene expression, we demonstrate that activation or repression of individual genes is unlikely to be controlled by a single ncRNA.
    DOI:  https://doi.org/10.1038/s41467-023-41848-9
  18. Nat Commun. 2023 Sep 26. 14(1): 5995
    Tracing immune cells around biomaterials with spatial anchors during large-scale wound regeneration.
    Yang Yang, Chenyu Chu, Li Liu, Chenbing Wang, Chen Hu, Shengan Rung, Yi Man, Yili Qu.
      Skin scarring devoid of dermal appendages after severe trauma has unfavorable effects on aesthetic and physiological functions. Here we present a method for large-area wound regeneration using biodegradable aligned extracellular matrix scaffolds. We show that the implantation of these scaffolds accelerates wound coverage and enhances hair follicle neogenesis. We perform multimodal analysis, in combination with single-cell RNA sequencing and spatial transcriptomics, to explore the immune responses around biomaterials, highlighting the potential role of regulatory T cells in mitigating tissue fibrous by suppressing excessive type 2 inflammation. We find that immunodeficient mice lacking mature T lymphocytes show the typical characteristic of tissue fibrous driven by type 2 macrophage inflammation, validating the potential therapeutic effect of the adaptive immune system activated by biomaterials. These findings contribute to our understanding of the coordination of immune systems in wound regeneration and facilitate the design of immunoregulatory biomaterials in the future.
    DOI:  https://doi.org/10.1038/s41467-023-41608-9
  19. Nat Commun. 2023 Sep 29. 14(1): 6086
    Multi-omics profiling reveals rhythmic liver function shaped by meal timing.
    Rongfeng Huang, Jianghui Chen, Meiyu Zhou, Haoran Xin, Sin Man Lam, Xiaoqing Jiang, Jie Li, Fang Deng, Guanghou Shui, Zhihui Zhang, Min-Dian Li.
      Post-translational modifications (PTMs) couple feed-fast cycles to diurnal rhythms. However, it remains largely uncharacterized whether and how meal timing organizes diurnal rhythms beyond the transcriptome. Here, we systematically profile the daily rhythms of the proteome, four PTMs (phosphorylation, ubiquitylation, succinylation and N-glycosylation) and the lipidome in the liver from young female mice subjected to either day/sleep time-restricted feeding (DRF) or night/wake time-restricted feeding (NRF). We detect robust daily rhythms among different layers of omics with phosphorylation the most nutrient-responsive and succinylation the least. Integrative analyses reveal that clock regulation of fatty acid metabolism represents a key diurnal feature that is reset by meal timing, as indicated by the rhythmic phosphorylation of the circadian repressor PERIOD2 at Ser971 (PER2-pSer971). We confirm that PER2-pSer971 is activated by nutrient availability in vivo. Together, this dataset represents a comprehensive resource detailing the proteomic and lipidomic responses by the liver to alterations in meal timing.
    DOI:  https://doi.org/10.1038/s41467-023-41759-9
  20. Nature. 2023 Sep 27.
    Proteome census upon nutrient stress reveals Golgiphagy membrane receptors.
    Kelsey L Hickey, Sharan Swarup, Ian R Smith, Julia C Paoli, Enya Miguel Whelan, Joao A Paulo, J Wade Harper.
      During nutrient stress, macroautophagy degrades cellular macromolecules, thereby providing biosynthetic building blocks while simultaneously remodeling the proteome1,2. While machinery responsible for initiation of macroautophagy is well characterized3,4, our understanding of the extent to which individual proteins, protein complexes and organelles are selected for autophagic degradation, and the underlying targeting mechanisms is limited. Here, we use orthogonal proteomic strategies to provide a spatial proteome census of autophagic cargo during nutrient stress in mammalian cells. We find that macroautophagy has selectivity for recycling membrane-bound organelles (principally Golgi and ER). Through autophagic cargo prioritization, we identify a complex of membrane-embedded proteins, YIPF3 and YIPF4, as receptors for Golgiphagy. During nutrient stress, YIPF3 and YIPF4 interact with ATG8s via LIR motifs and are mobilized into autophagosomes that traffic to lysosomes in a process that requires the canonical autophagic machinery. Cells lacking YIPF3 or YIPF4 are selectively defective in elimination of a specific cohort of Golgi membrane proteins during nutrient stress. Moreover, YIPF3/4 play an analogous role in Golgi remodeling during programmed conversion of stem cells to the neuronal lineage in vitro. Collectively, this study reveals prioritization of membrane protein cargo during nutrient stress-dependent proteome remodeling and identifies an unanticipated Golgi remodeling pathway requiring membrane-embedded receptors.
    DOI:  https://doi.org/10.1038/s41586-023-06657-6
  21. Nat Commun. 2023 09 23. 14(1): 5947
    The leaderless communication peptide (LCP) class of quorum-sensing peptides is broadly distributed among Firmicutes.
    Shifu Aggarwal, Elaine Huang, Hackwon Do, Nishanth Makthal, Yanyan Li, Eric Bapteste, Philippe Lopez, Charles Bernard, Muthiah Kumaraswami.
      The human pathogen Streptococcus pyogenes secretes a short peptide (leaderless communication peptide, LCP) that mediates intercellular communication and controls bacterial virulence through interaction with its receptor, RopB. Here, we show that LCP and RopB homologues are present in other Firmicutes. We experimentally validate that LCPs with distinct peptide communication codes act as bacterial intercellular signals and regulate gene expression in Streptococcus salivarius, Streptococcus porcinus, Enterococcus malodoratus and Limosilactobacillus reuteri. Our results indicate that LCPs are more widespread than previously thought, and their characterization may uncover new signaling mechanisms and roles in coordinating diverse bacterial traits.
    DOI:  https://doi.org/10.1038/s41467-023-41719-3
  22. Nat Metab. 2023 Sep 28.
    Functional screening and rational design of compounds targeting GPR132 to treat diabetes.
    Jia-Le Wang, Xiao-Dong Dou, Jie Cheng, Ming-Xin Gao, Guo-Feng Xu, Wei Ding, Jin-Hui Ding, Yu Li, Si-Han Wang, Zhao-Wei Ji, Xin-Yi Zhao, Tong-Yu Huo, Cai-Fang Zhang, Ya-Meng Liu, Xue-Ying Sha, Jia-Rui Gao, Wen-Hui Zhang, Yong Hao, Cheng Zhang, Jin-Peng Sun, Ning Jiao, Xiao Yu.
      Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes.
    DOI:  https://doi.org/10.1038/s42255-023-00899-4
  23. Nature. 2023 Sep 28.
    The brain cells linked to protection against dementia.
    Sara Reardon.
      
    Keywords:  Ageing; Alzheimer's disease; Brain; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-023-03012-7
  24. Nat Commun. 2023 Sep 27. 14(1): 6036
    All-optical spatiotemporal mapping of ROS dynamics across mitochondrial microdomains in situ.
    Shon A Koren, Nada Ahmed Selim, Lizbeth De la Rosa, Jacob Horn, M Arsalan Farooqi, Alicia Y Wei, Annika Müller-Eigner, Jacen Emerson, Gail V W Johnson, Andrew P Wojtovich.
      Hydrogen peroxide (H2O2) functions as a second messenger to signal metabolic distress through highly compartmentalized production in mitochondria. The dynamics of reactive oxygen species (ROS) generation and diffusion between mitochondrial compartments and into the cytosol govern oxidative stress responses and pathology, though these processes remain poorly understood. Here, we couple the H2O2 biosensor, HyPer7, with optogenetic stimulation of the ROS-generating protein KillerRed targeted into multiple mitochondrial microdomains. Single mitochondrial photogeneration of H2O2 demonstrates the spatiotemporal dynamics of ROS diffusion and transient hyperfusion of mitochondria due to ROS. This transient hyperfusion phenotype required mitochondrial fusion but not fission machinery. Measurement of microdomain-specific H2O2 diffusion kinetics reveals directionally selective diffusion through mitochondrial microdomains. All-optical generation and detection of physiologically-relevant concentrations of H2O2 between mitochondrial compartments provide a map of mitochondrial H2O2 diffusion dynamics in situ as a framework to understand the role of ROS in health and disease.
    DOI:  https://doi.org/10.1038/s41467-023-41682-z
  25. Cell. 2023 Sep 28. pii: S0092-8674(23)00972-8. [Epub ahead of print]186(20): 4404-4421.e20
    Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration.
    Vishnu Dileep, Carles A Boix, Hansruedi Mathys, Asaf Marco, Gwyneth M Welch, Hiruy S Meharena, Anjanet Loon, Ritika Jeloka, Zhuyu Peng, David A Bennett, Manolis Kellis, Li-Huei Tsai.
      Persistent DNA double-strand breaks (DSBs) in neurons are an early pathological hallmark of neurodegenerative diseases including Alzheimer's disease (AD), with the potential to disrupt genome integrity. We used single-nucleus RNA-seq in human postmortem prefrontal cortex samples and found that excitatory neurons in AD were enriched for somatic mosaic gene fusions. Gene fusions were particularly enriched in excitatory neurons with DNA damage repair and senescence gene signatures. In addition, somatic genome structural variations and gene fusions were enriched in neurons burdened with DSBs in the CK-p25 mouse model of neurodegeneration. Neurons enriched for DSBs also had elevated levels of cohesin along with progressive multiscale disruption of the 3D genome organization aligned with transcriptional changes in synaptic, neuronal development, and histone genes. Overall, this study demonstrates the disruption of genome stability and the 3D genome organization by DSBs in neurons as pathological steps in the progression of neurodegenerative diseases.
    Keywords:  3D genome organization; Alzheimer’s disease; DNA double-strand breaks; epigenome; genome rearrangements; genomic mosaicism; neurodegeneration; senescence; structural variations; transcriptome
    DOI:  https://doi.org/10.1016/j.cell.2023.08.038
  26. Nat Commun. 2023 Sep 25. 14(1): 5978
    On the visual analytic intelligence of neural networks.
    Stanisław Woźniak, Hlynur Jónsson, Giovanni Cherubini, Angeliki Pantazi, Evangelos Eleftheriou.
      Visual oddity task was conceived to study universal ethnic-independent analytic intelligence of humans from a perspective of comprehension of spatial concepts. Advancements in artificial intelligence led to important breakthroughs, yet excelling at such abstract tasks remains challenging. Current approaches typically resort to non-biologically-plausible architectures with ever-growing models consuming substantially more energy than the brain. Motivated by the brain's efficiency and reasoning capabilities, we present a biologically inspired system that receives inputs from synthetic eye movements - reminiscent of saccades, and processes them with neuronal units incorporating dynamics of neocortical neurons. We introduce a procedurally generated visual oddity dataset to train an architecture extending conventional relational networks and our proposed system. We demonstrate that both approaches are capable of abstract problem-solving at high accuracy, and we uncover that both share the same essential underlying mechanism of reasoning in seemingly unrelated aspects of their architectures. Finally, we show that the biologically inspired network achieves superior accuracy, learns faster and requires fewer parameters than the conventional network.
    DOI:  https://doi.org/10.1038/s41467-023-41566-2
  27. Nat Commun. 2023 Sep 26. 14(1): 6009
    Patient-specific models link neurotransmitter receptor mechanisms with motor and visuospatial axes of Parkinson's disease.
    Ahmed Faraz Khan, Quadri Adewale, Sue-Jin Lin, Tobias R Baumeister, Yashar Zeighami, Felix Carbonell, Nicola Palomero-Gallagher, Yasser Iturria-Medina.
      Parkinson's disease involves multiple neurotransmitter systems beyond the classical dopaminergic circuit, but their influence on structural and functional alterations is not well understood. Here, we use patient-specific causal brain modeling to identify latent neurotransmitter receptor-mediated mechanisms contributing to Parkinson's disease progression. Combining the spatial distribution of 15 receptors from post-mortem autoradiography with 6 neuroimaging-derived pathological factors, we detect a diverse set of receptors influencing gray matter atrophy, functional activity dysregulation, microstructural degeneration, and dendrite and dopaminergic transporter loss. Inter-individual variability in receptor mechanisms correlates with symptom severity along two distinct axes, representing motor and psychomotor symptoms with large GABAergic and glutamatergic contributions, and cholinergically-dominant visuospatial, psychiatric and memory dysfunction. Our work demonstrates that receptor architecture helps explain multi-factorial brain re-organization, and suggests that distinct, co-existing receptor-mediated processes underlie Parkinson's disease.
    DOI:  https://doi.org/10.1038/s41467-023-41677-w
  28. Cell. 2023 Sep 28. pii: S0092-8674(23)00979-0. [Epub ahead of print]186(20): 4257-4259
    The AD odyssey 2023: Tales of single cell.
    Wenjie Luo, Wenhui Qu, Li Gan.
      Deciphering cellular changes in Alzheimer's disease (AD) using large cohorts with defined clinical stages is essential for understanding the diverse trajectories of AD progression. In this issue of Cell, five studies harnessed the power of single-nuclei RNA sequencing (snRNA-seq) and single-nuclei ATAC sequencing (snATAC-seq) at unprecedented scale and revealed exciting insights into cell-type-specific mechanisms underlying the progression of AD pathogenesis.
    DOI:  https://doi.org/10.1016/j.cell.2023.09.001
  29. Cell Rep. 2023 Sep 26. pii: S2211-1247(23)01183-X. [Epub ahead of print]42(10): 113171
    Myeloid BAF60a deficiency alters metabolic homeostasis and exacerbates atherosclerosis.
    Yang Zhao, Yuhao Liu, Guizhen Zhao, Haocheng Lu, Yaozhong Liu, Chao Xue, Ziyi Chang, Hongyu Liu, Yongjie Deng, Wenying Liang, Huilun Wang, Oren Rom, Minerva T Garcia-Barrio, Tianqing Zhu, Yanhong Guo, Lin Chang, Jiandie Lin, Y Eugene Chen, Jifeng Zhang.
      Atherosclerosis, a leading health concern, stems from the dynamic involvement of immune cells in vascular plaques. Despite its significance, the interplay between chromatin remodeling and transcriptional regulation in plaque macrophages is understudied. We discovered the reduced expression of Baf60a, a component of the switch/sucrose non-fermentable (SWI/SNF) chromatin remodeling complex, in macrophages from advanced plaques. Myeloid-specific Baf60a deletion compromised mitochondrial integrity and heightened adhesion, apoptosis, and plaque development. BAF60a preserves mitochondrial energy homeostasis under pro-atherogenic stimuli by retaining nuclear respiratory factor 1 (NRF1) accessibility at critical genes. Overexpression of BAF60a rescued mitochondrial dysfunction in an NRF1-dependent manner. This study illuminates the BAF60a-NRF1 axis as a mitochondrial function modulator in atherosclerosis, proposing the rejuvenation of perturbed chromatin remodeling machinery as a potential therapeutic target.
    Keywords:  CP: Metabolism; CP: Molecular biology; SWI/SNF; atherosclerosis; chromatin remodeling; macrophage; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2023.113171
  30. Nat Aging. 2023 Sep 28.
    Co-designing to enable modern aging.
    Global Centre for Modern Ageing (GCMA)
      
    DOI:  https://doi.org/10.1038/s43587-023-00494-y
  31. Nat Cell Biol. 2023 Sep 28.
    Regulators of mitonuclear balance link mitochondrial metabolism to mtDNA expression.
    Nicholas J Kramer, Gyan Prakash, R Stefan Isaac, Karine Choquet, Iliana Soto, Boryana Petrova, Hope E Merens, Naama Kanarek, L Stirling Churchman.
      Mitochondrial oxidative phosphorylation (OXPHOS) complexes are assembled from proteins encoded by both nuclear and mitochondrial DNA. These dual-origin enzymes pose a complex gene regulatory challenge for cells requiring coordinated gene expression across organelles. To identify genes involved in dual-origin protein complex synthesis, we performed fluorescence-activated cell-sorting-based genome-wide screens analysing mutant cells with unbalanced levels of mitochondrial- and nuclear-encoded subunits of Complex IV. We identified genes involved in OXPHOS biogenesis, including two uncharacterized genes: PREPL and NME6. We found that PREPL specifically impacts Complex IV biogenesis by acting at the intersection of mitochondrial lipid metabolism and protein synthesis, whereas NME6, an uncharacterized nucleoside diphosphate kinase, controls OXPHOS biogenesis through multiple mechanisms reliant on its NDPK domain. Firstly, NME6 forms a complex with RCC1L, which together perform nucleoside diphosphate kinase activity to maintain local mitochondrial pyrimidine triphosphate levels essential for mitochondrial RNA abundance. Secondly, NME6 modulates the activity of mitoribosome regulatory complexes, altering mitoribosome assembly and mitochondrial RNA pseudouridylation. Taken together, we propose that NME6 acts as a link between compartmentalized mitochondrial metabolites and mitochondrial gene expression.
    DOI:  https://doi.org/10.1038/s41556-023-01244-3
  32. Nat Commun. 2023 Sep 25. 14(1): 5963
    A Glycolipidated-liposomal peptide vaccine confers long-term mucosal protection against Streptococcus pyogenes via IL-17, macrophages and neutrophils.
    Victoria Ozberk, Mehfuz Zaman, Ailin Lepletier, Sharareh Eskandari, Jacqualine Kaden, Jamie-Lee Mills, Ainslie Calcutt, Jessica Dooley, Yongbao Huo, Emma L Langshaw, Glen C Ulett, Michael R Batzloff, Michael F Good, Manisha Pandey.
      Mucosally active subunit vaccines are an unmet clinical need due to lack of licensed immunostimulants suitable for vaccine antigens. Here, we show that intranasal administration of liposomes incorporating: the Streptococcus pyogenes peptide antigen, J8; diphtheria toxoid as a source of T cell help; and the immunostimulatory glycolipid, 3D(6-acyl) PHAD (PHAD), is able to induce long-lived humoral and cellular immunity. Mice genetically deficient in either mucosal antibodies or total antibodies are protected against S. pyogenes respiratory tract infection. Utilizing IL-17-deficient mice or depleting cellular subsets using antibodies, shows that the cellular responses encompassing, CD4+ T cells, IL-17, macrophages and neutrophils have important functions in vaccine-mediated mucosal immunity. Overall, these data demonstrate the utility of a mucosal vaccine platform to deliver multi-pronged protective responses against a highly virulent pathogen.
    DOI:  https://doi.org/10.1038/s41467-023-41410-7
  33. Dev Cell. 2023 Sep 25. pii: S1534-5807(23)00438-0. [Epub ahead of print]58(18): 1701-1715.e8
    Single-cell epigenome analysis identifies molecular events controlling direct conversion of human fibroblasts to pancreatic ductal-like cells.
    Liangru Fei, Kaiyang Zhang, Nikita Poddar, Sampsa Hautaniemi, Biswajyoti Sahu.
      Cell fate can be reprogrammed by ectopic expression of lineage-specific transcription factors (TFs). However, the exact cell state transitions during transdifferentiation are still poorly understood. Here, we have generated pancreatic exocrine cells of ductal epithelial identity from human fibroblasts using a set of six TFs. We mapped the molecular determinants of lineage dynamics using a factor-indexing method based on single-nuclei multiome sequencing (FI-snMultiome-seq) that enables dissecting the role of each individual TF and pool of TFs in cell fate conversion. We show that transition from mesenchymal fibroblast identity to epithelial pancreatic exocrine fate involves two deterministic steps: an endodermal progenitor state defined by activation of HHEX with FOXA2 and SOX17 and a temporal GATA4 activation essential for the maintenance of pancreatic cell fate program. Collectively, our data suggest that transdifferentiation-although being considered a direct cell fate conversion method-occurs through transient progenitor states orchestrated by stepwise activation of distinct TFs.
    Keywords:  cell fate; direct reprogramming; epigenetics; exocrine pancreas; gene regulation; single-cell multiome sequencing; transcription factor
    DOI:  https://doi.org/10.1016/j.devcel.2023.08.023
  34. Sci Immunol. 2023 Sep 29. 8(87): eadd1599
    NKG2D-mediated detection of metabolically stressed hepatocytes by innate-like T cells is essential for initiation of NASH and fibrosis.
    Sonja Marinović, Maja Lenartić, Karlo Mladenić, Marko Šestan, Inga Kavazović, Ante Benić, Mia Krapić, Lukas Rindlisbacher, Maja Cokarić Brdov Ak, Colin Sparano, Gioana Litscher, Tamara Turk Wensveen, Ivana Mikolašević, Dora Fǔkar Čupić, Lidija Bilić-Zulle, Aleksander Steinle, Ari Waisman, Adrian Hayday, Sonia Tugues, Burkhard Becher, Bojan Polić, Felix M Wensveen.
      Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A+ γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD.
    DOI:  https://doi.org/10.1126/sciimmunol.add1599
  35. Cell. 2023 Sep 28. pii: S0092-8674(23)00974-1. [Epub ahead of print]186(20): 4422-4437.e21
    Epigenomic dissection of Alzheimer's disease pinpoints causal variants and reveals epigenome erosion.
    Xushen Xiong, Benjamin T James, Carles A Boix, Yongjin P Park, Kyriaki Galani, Matheus B Victor, Na Sun, Lei Hou, Li-Lun Ho, Julio Mantero, Aine Ni Scannail, Vishnu Dileep, Weixiu Dong, Hansruedi Mathys, David A Bennett, Li-Huei Tsai, Manolis Kellis.
      Recent work has identified dozens of non-coding loci for Alzheimer's disease (AD) risk, but their mechanisms and AD transcriptional regulatory circuitry are poorly understood. Here, we profile epigenomic and transcriptomic landscapes of 850,000 nuclei from prefrontal cortexes of 92 individuals with and without AD to build a map of the brain regulome, including epigenomic profiles, transcriptional regulators, co-accessibility modules, and peak-to-gene links in a cell-type-specific manner. We develop methods for multimodal integration and detecting regulatory modules using peak-to-gene linking. We show AD risk loci are enriched in microglial enhancers and for specific TFs including SPI1, ELF2, and RUNX1. We detect 9,628 cell-type-specific ATAC-QTL loci, which we integrate alongside peak-to-gene links to prioritize AD variant regulatory circuits. We report differential accessibility of regulatory modules in late AD in glia and in early AD in neurons. Strikingly, late-stage AD brains show global epigenome dysregulation indicative of epigenome erosion and cell identity loss.
    Keywords:  ATAC-QTL; Alzheimer’s disease; GWAS; epigenome; epigenome erosion; fine-mapping; multimodal integration; peak-to-gene linking
    DOI:  https://doi.org/10.1016/j.cell.2023.08.040
  36. Nat Genet. 2023 Sep 28.
    Multitissue H3K27ac profiling of GTEx samples links epigenomic variation to disease.
    Lei Hou, Xushen Xiong, Yongjin Park, Carles Boix, Benjamin James, Na Sun, Liang He, Aman Patel, Zhizhuo Zhang, Benoit Molinie, Nicholas Van Wittenberghe, Scott Steelman, Chad Nusbaum, François Aguet, Kristin G Ardlie, Manolis Kellis.
      Genetic variants associated with complex traits are primarily noncoding, and their effects on gene-regulatory activity remain largely uncharacterized. To address this, we profile epigenomic variation of histone mark H3K27ac across 387 brain, heart, muscle and lung samples from Genotype-Tissue Expression (GTEx). We annotate 282 k active regulatory elements (AREs) with tissue-specific activity patterns. We identify 2,436 sex-biased AREs and 5,397 genetically influenced AREs associated with 130 k genetic variants (haQTLs) across tissues. We integrate genetic and epigenomic variation to provide mechanistic insights for disease-associated loci from 55 genome-wide association studies (GWAS), by revealing candidate tissues of action, driver SNPs and impacted AREs. Lastly, we build ARE-gene linking scores based on genetics (gLink scores) and demonstrate their unique ability to prioritize SNP-ARE-gene circuits. Overall, our epigenomic datasets, computational integration and mechanistic predictions provide valuable resources and important insights for understanding the molecular basis of human diseases/traits such as schizophrenia.
    DOI:  https://doi.org/10.1038/s41588-023-01509-5
  37. Nature. 2023 Sep 25.
    How Dolly the sheep's legacy lives on: CRISPR cattle and cloned camels.
    Heidi Ledford.
      
    Keywords:  Biological techniques; Biotechnology; Genetics
    DOI:  https://doi.org/10.1038/d41586-023-02921-x
  38. Commun Biol. 2023 09 23. 6(1): 975
    GiRAFR improves gRNA detection and annotation in single-cell CRISPR screens.
    Qian Yu, Paulien Van Minsel, Eva Galle, Bernard Thienpont.
      Novel methods that combine single cell RNA-seq with CRISPR screens enable high-throughput characterization of transcriptional changes caused by genetic perturbations. Dedicated software is however lacking to annotate CRISPR guide RNA (gRNA) libraries and associate them with single cell transcriptomes. Here, we describe a CRISPR droplet sequencing (CROP-seq) dataset. During analysis, we observed that the most commonly used method fails to detect mutant gRNAs. We therefore developed a python tool to identify and characterize intact and mutant gRNAs, called GiRAFR. We show that mutant gRNAs are dysfunctional, and failure to detect and annotate them leads to an inflated estimate of the number of untransformed cells, attenuated downregulation of target genes, as well as an underestimated multiplet frequency. These findings are mirrored in publicly available datasets, where we find that up to 35% of cells are transduced with a mutant gRNA. Applying GiRAFR hence stands to improve the annotation and quality of single cell CRISPR screens.
    DOI:  https://doi.org/10.1038/s42003-023-05351-7
  39. Nature. 2023 Sep 27.
    The very first beat: how a heart starts to pulse.
    Shamini Bundell.
      
    Keywords:  Developmental biology; Genetics; Health care
    DOI:  https://doi.org/10.1038/d41586-023-03052-z
  40. Science. 2023 Sep 29. 381(6665): 1440-1445
    An evolutionary epigenetic clock in plants.
    N Yao, Z Zhang, L Yu, R Hazarika, C Yu, H Jang, L M Smith, J Ton, L Liu, J J Stachowicz, T B H Reusch, R J Schmitz, F Johannes.
      Molecular clocks are the basis for dating the divergence between lineages over macroevolutionary timescales (~105 to 108 years). However, classical DNA-based clocks tick too slowly to inform us about the recent past. Here, we demonstrate that stochastic DNA methylation changes at a subset of cytosines in plant genomes display a clocklike behavior. This "epimutation clock" is orders of magnitude faster than DNA-based clocks and enables phylogenetic explorations on a scale of years to centuries. We show experimentally that epimutation clocks recapitulate known topologies and branching times of intraspecies phylogenetic trees in the self-fertilizing plant Arabidopsis thaliana and the clonal seagrass Zostera marina, which represent two major modes of plant reproduction. This discovery will open new possibilities for high-resolution temporal studies of plant biodiversity.
    DOI:  https://doi.org/10.1126/science.adh9443
  41. Nat Commun. 2023 09 23. 14(1): 5944
    Epitranscriptomic subtyping, visualization, and denoising by global motif visualization.
    Jianheng Liu, Tao Huang, Jing Yao, Tianxuan Zhao, Yusen Zhang, Rui Zhang.
      Advances in sequencing technologies have empowered epitranscriptomic profiling at the single-base resolution. Putative RNA modification sites identified from a single high-throughput experiment may contain one type of modification deposited by different writers or different types of modifications, along with false positive results because of the challenge of distinguishing signals from noise. However, current tools are insufficient for subtyping, visualization, and denoising these signals. Here, we present iMVP, which is an interactive framework for epitranscriptomic analysis with a nonlinear dimension reduction technique and density-based partition. As exemplified by the analysis of mRNA m5C and ModTect variant data, we show that iMVP allows the identification of previously unknown RNA modification motifs and writers and the discovery of false positives that are undetectable by traditional methods. Using putative m6A/m6Am sites called from 8 profiling approaches, we illustrate that iMVP enables comprehensive comparison of different approaches and advances our understanding of the difference and pattern of true positives and artifacts in these methods. Finally, we demonstrate the ability of iMVP to analyze an extremely large human A-to-I editing dataset that was previously unmanageable. Our work provides a general framework for the visualization and interpretation of epitranscriptomic data.
    DOI:  https://doi.org/10.1038/s41467-023-41653-4
  42. Nat Immunol. 2023 Oct;24(10): 1606-1609
    γδ T cell explorations seek terra firma.
    Bruno Silva-Santos, Julie C Ribot, Erin J Adams, Benjamin E Willcox, Matthias Eberl.
      
    DOI:  https://doi.org/10.1038/s41590-023-01606-x
  43. Nat Genet. 2023 Sep 28.
    Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.
    Maryam Kavousi, Maxime M Bos, Hanna J Barnes, Christian L Lino Cardenas, Doris Wong, Haojie Lu, Chani J Hodonsky, Lennart P L Landsmeer, Adam W Turner, Minjung Kho, Natalie R Hasbani, Paul S de Vries, Donald W Bowden, Sandesh Chopade, Joris Deelen, Ernest Diez Benavente, Xiuqing Guo, Edith Hofer, Shih-Jen Hwang, Sharon M Lutz, Leo-Pekka Lyytikäinen, Lotte Slenders, Albert V Smith, Maggie A Stanislawski, Jessica van Setten, Quenna Wong, Lisa R Yanek, Diane M Becker, Marian Beekman, Matthew J Budoff, Mary F Feitosa, Chris Finan, Austin T Hilliard, Sharon L R Kardia, Jason C Kovacic, Brian G Kral, Carl D Langefeld, Lenore J Launer, Shaista Malik, Firdaus A A Mohamed Hoesein, Michal Mokry, Reinhold Schmidt, Jennifer A Smith, Kent D Taylor, James G Terry, Jeroen van der Grond, Joyce van Meurs, Rozemarijn Vliegenthart, Jianzhao Xu, Kendra A Young, Nuno R Zilhão, Robert Zweiker, Themistocles L Assimes, Lewis C Becker, Daniel Bos, J Jeffrey Carr, L Adrienne Cupples, Dominique P V de Kleijn, Menno de Winther, Hester M den Ruijter, Myriam Fornage, Barry I Freedman, Vilmundur Gudnason, Aroon D Hingorani, John E Hokanson, M Arfan Ikram, Ivana Išgum, David R Jacobs, Mika Kähönen, Leslie A Lange, Terho Lehtimäki, Gerard Pasterkamp, Olli T Raitakari, Helena Schmidt, P Eline Slagboom, André G Uitterlinden, Meike W Vernooij, Joshua C Bis, Nora Franceschini, Bruce M Psaty, Wendy S Post, Jerome I Rotter, Johan L M Björkegren, Christopher J O'Donnell, Lawrence F Bielak, Patricia A Peyser, Rajeev Malhotra, Sander W van der Laan, Clint L Miller.
      Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.
    DOI:  https://doi.org/10.1038/s41588-023-01518-4
  44. Immunology. 2023 Sep 27.
    Suppression of protein quality control system by TRIM30a sensitises tumour cells to NK cell-mediated immune surveillance.
    Lukman O Afolabi, Jiacheng Bi, Liang Chen, Xiaolu Yang, Xiaochun Wan.
      Tumorigenesis entails circumventing cell-intrinsic regulatory mechanisms while avoiding extrinsic immune surveillance and other host defence systems. Nevertheless, how tumour cells' ability to eliminate misfolded proteins affects immune surveillance remains poorly understood. In this study, we find that overexpression of murine tripartite motif-containing protein 30a (TRIM30a) sensitises tumour cells to natural killer (NK) cells-mediated cytolysis. TRIM30a has no effect on tumour cell proliferation or apoptosis in vitro. However, TRIM30a-overexpressing tumour cells grow substantially slower than control tumour cells in immune-competent mice but not in NK-depleted mice. Mechanistically, TRIM30a overexpression impedes the clearance of misfolded protein and increases the production of reactive oxygen species induced by proteotoxic stress, implying that TRIM30a impairs protein quality control (PQC) systems in tumour cells. Furthermore, TRIM30a reduces expression of genes encoding proteasome subunits and antioxidant proteins. Our study demonstrates that TRIM30a is a potential tumour suppressor and immune modulator that promotes tumour cytolysis by NK cells, and suggests that an enhanced PQC and antioxidant capacity is an integral part of the immune escape mechanism during tumorigenesis.
    Keywords:  antioxidant response element; cytotoxicity; natural killer cell; proteasome; protein quality control; tripartite motif-containing protein 30a
    DOI:  https://doi.org/10.1111/imm.13694
  45. Nat Commun. 2023 09 26. 14(1): 5712
    Engineering microbial division of labor for plastic upcycling.
    Teng Bao, Yuanchao Qian, Yongping Xin, James J Collins, Ting Lu.
      Plastic pollution is rapidly increasing worldwide, causing adverse impacts on the environment, wildlife and human health. One tempting solution to this crisis is upcycling plastics into products with engineered microorganisms; however, this remains challenging due to complexity in conversion. Here we present a synthetic microbial consortium that efficiently degrades polyethylene terephthalate hydrolysate and subsequently produces desired chemicals through division of labor. The consortium involves two Pseudomonas putida strains, specializing in terephthalic acid and ethylene glycol utilization respectively, to achieve complete substrate assimilation. Compared with its monoculture counterpart, the consortium exhibits reduced catabolic crosstalk and faster deconstruction, particularly when substrate concentrations are high or crude hydrolysate is used. It also outperforms monoculture when polyhydroxyalkanoates serves as a target product and confers flexible tuning through population modulation for cis-cis muconate synthesis. This work demonstrates engineered consortia as a promising, effective platform that may facilitate polymer upcycling and environmental sustainability.
    DOI:  https://doi.org/10.1038/s41467-023-40777-x
  46. Cell. 2023 Sep 28. pii: S0092-8674(23)00973-X. [Epub ahead of print]186(20): 4365-4385.e27
    Single-cell atlas reveals correlates of high cognitive function, dementia, and resilience to Alzheimer's disease pathology.
    Hansruedi Mathys, Zhuyu Peng, Carles A Boix, Matheus B Victor, Noelle Leary, Sudhagar Babu, Ghada Abdelhady, Xueqiao Jiang, Ayesha P Ng, Kimia Ghafari, Alexander K Kunisky, Julio Mantero, Kyriaki Galani, Vanshika N Lohia, Gabrielle E Fortier, Yasmine Lotfi, Jason Ivey, Hannah P Brown, Pratham R Patel, Nehal Chakraborty, Jacob I Beaudway, Elizabeth J Imhoff, Cameron F Keeler, Maren M McChesney, Haishal H Patel, Sahil P Patel, Megan T Thai, David A Bennett, Manolis Kellis, Li-Huei Tsai.
      Alzheimer's disease (AD) is the most common cause of dementia worldwide, but the molecular and cellular mechanisms underlying cognitive impairment remain poorly understood. To address this, we generated a single-cell transcriptomic atlas of the aged human prefrontal cortex covering 2.3 million cells from postmortem human brain samples of 427 individuals with varying degrees of AD pathology and cognitive impairment. Our analyses identified AD-pathology-associated alterations shared between excitatory neuron subtypes, revealed a coordinated increase of the cohesin complex and DNA damage response factors in excitatory neurons and in oligodendrocytes, and uncovered genes and pathways associated with high cognitive function, dementia, and resilience to AD pathology. Furthermore, we identified selectively vulnerable somatostatin inhibitory neuron subtypes depleted in AD, discovered two distinct groups of inhibitory neurons that were more abundant in individuals with preserved high cognitive function late in life, and uncovered a link between inhibitory neurons and resilience to AD pathology.
    Keywords:  Alzheimer's disease; DNA damage response; cognitive impairment; cognitive resilience; cohesin complex; inhibitory neurons; neurodegeneration; single-cell transcriptomic atlas
    DOI:  https://doi.org/10.1016/j.cell.2023.08.039
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