bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–02–19
37 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Human cell-type methylomes.
  2. A NPAS4-NuA4 complex couples synaptic activity to DNA repair.
  3. Linking viruses with neurodegeneration.
  4. Genetics of sexually dimorphic adipose distribution in humans.
  5. Microglia C-lectin/selectin' neurons to eat.
  6. DddA homolog search and engineering expand sequence compatibility of mitochondrial base editing.
  7. Decoding foreign antigen tolerance.
  8. Directed self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes.
  9. Structural basis for membrane attack complex inhibition by CD59.
  10. SVEP1 is an endogenous ligand for the orphan receptor PEAR1.
  11. Infection induces tissue-resident memory NK cells that safeguard tissue health.
  12. Deconstructing the modular organization and real-time dynamics of mammalian spinal locomotor networks.
  13. TACCO unifies annotation transfer and decomposition of cell identities for single-cell and spatial omics.
  14. Cross-protective antibodies against common endemic respiratory viruses.
  15. The ubiquitination landscape of the influenza A virus polymerase.
  16. Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice.
  17. A trans-kingdom T6SS effector induces the fragmentation of the mitochondrial network and activates innate immune receptor NLRX1 to promote infection.
  18. Multiscale 3D genome reorganization during skeletal muscle stem cell lineage progression and aging.
  19. Mitochondrial single-cell ATAC-seq for high-throughput multi-omic detection of mitochondrial genotypes and chromatin accessibility.
  20. Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer's disease.
  21. gutSMASH predicts specialized primary metabolic pathways from the human gut microbiota.
  22. Reverse electron transfer is activated during aging and contributes to aging and age-related disease.
  23. Association and Interaction of Genetics and Area-Level Socioeconomic Factors on the Prevalence of Type 2 Diabetes and Obesity.
  24. Network of hotspot interactions cluster tau amyloid folds.
  25. 'Mirror neurons' fire up during mouse battles.
  26. Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers.
  27. CD5 expression by dendritic cells directs T cell immunity and sustains immunotherapy responses.
  28. Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus.
  29. IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases.
  30. T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles.
  31. IL-1/MyD88-Dependent G-CSF and IL-6 Secretion Mediates Postburn Anemia.
  32. Decoding the diversity of killer immunoglobulin-like receptors by deep sequencing and a high-resolution imputation method.
  33. Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation.
  34. Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines.
  35. Fragile-like regulatory T cells modulate opioid withdrawal in humans and mice.
  36. Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice.
  37. Multi-ancestry meta-analysis of asthma identifies novel associations and highlights the value of increased power and diversity.
  1. Nat Genet. 2023 Feb;55(2): 167
    Human cell-type methylomes.
    Wei Li.
      
    DOI:  https://doi.org/10.1038/s41588-023-01311-3
  2. Nature. 2023 Feb 15.
    A NPAS4-NuA4 complex couples synaptic activity to DNA repair.
    Elizabeth A Pollina, Daniel T Gilliam, Andrew T Landau, Cindy Lin, Naomi Pajarillo, Christopher P Davis, David A Harmin, Ee-Lynn Yap, Ian R Vogel, Eric C Griffith, M Aurel Nagy, Emi Ling, Erin E Duffy, Bernardo L Sabatini, Charles J Weitz, Michael E Greenberg.
      Neuronal activity is crucial for adaptive circuit remodelling but poses an inherent risk to the stability of the genome across the long lifespan of postmitotic neurons1-5. Whether neurons have acquired specialized genome protection mechanisms that enable them to withstand decades of potentially damaging stimuli during periods of heightened activity is unknown. Here we identify an activity-dependent DNA repair mechanism in which a new form of the NuA4-TIP60 chromatin modifier assembles in activated neurons around the inducible, neuronal-specific transcription factor NPAS4. We purify this complex from the brain and demonstrate its functions in eliciting activity-dependent changes to neuronal transcriptomes and circuitry. By characterizing the landscape of activity-induced DNA double-strand breaks in the brain, we show that NPAS4-NuA4 binds to recurrently damaged regulatory elements and recruits additional DNA repair machinery to stimulate their repair. Gene regulatory elements bound by NPAS4-NuA4 are partially protected against age-dependent accumulation of somatic mutations. Impaired NPAS4-NuA4 signalling leads to a cascade of cellular defects, including dysregulated activity-dependent transcriptional responses, loss of control over neuronal inhibition and genome instability, which all culminate to reduce organismal lifespan. In addition, mutations in several components of the NuA4 complex are reported to lead to neurodevelopmental and autism spectrum disorders. Together, these findings identify a neuronal-specific complex that couples neuronal activity directly to genome preservation, the disruption of which may contribute to developmental disorders, neurodegeneration and ageing.
    DOI:  https://doi.org/10.1038/s41586-023-05711-7
  3. Nat Genet. 2023 Feb;55(2): 167
    Linking viruses with neurodegeneration.
    Kyle Vogan.
      
    DOI:  https://doi.org/10.1038/s41588-023-01312-2
  4. Nat Genet. 2023 Feb 16.
    Genetics of sexually dimorphic adipose distribution in humans.
    Grace T Hansen, Débora R Sobreira, Zachary T Weber, Alexis G Thornburg, Ivy Aneas, Li Zhang, Noboru J Sakabe, Amelia C Joslin, Gabriela A Haddad, Sophie M Strobel, Samantha Laber, Farhath Sultana, Faezeh Sahebdel, Kohinoor Khan, Yang I Li, Melina Claussnitzer, Liang Ye, Ricardo A Battaglino, Marcelo A Nóbrega.
      Obesity-associated morbidity is exacerbated by abdominal obesity, which can be measured as the waist-to-hip ratio adjusted for the body mass index (WHRadjBMI). Here we identify genes associated with obesity and WHRadjBMI and characterize allele-sensitive enhancers that are predicted to regulate WHRadjBMI genes in women. We found that several waist-to-hip ratio-associated variants map within primate-specific Alu retrotransposons harboring a DNA motif associated with adipocyte differentiation. This suggests that a genetic component of adipose distribution in humans may involve co-option of retrotransposons as adipose enhancers. We evaluated the role of the strongest female WHRadjBMI-associated gene, SNX10, in adipose biology. We determined that it is required for human adipocyte differentiation and function and participates in diet-induced adipose expansion in female mice, but not males. Our data identify genes and regulatory mechanisms that underlie female-specific adipose distribution and mediate metabolic dysfunction in women.
    DOI:  https://doi.org/10.1038/s41588-023-01306-0
  5. Immunity. 2023 Feb 14. pii: S1074-7613(23)00030-4. [Epub ahead of print]56(2): 227-229
    Microglia C-lectin/selectin' neurons to eat.
    Yike Jiang, Mari L Shinohara.
      β-glucosylceramide (β-GlcCer) accumulates in Gaucher disease, but how β-GlcCer, a Mincle ligand, causes characteristic neuroinflammation and neuronopathy is poorly understood. In this issue of Immunity, Shimizu et al. reveal that Mincle-dependent activation of microglia led to phagocytosis of neurons and neurologic symptoms.
    DOI:  https://doi.org/10.1016/j.immuni.2023.01.020
  6. Nat Commun. 2023 Feb 16. 14(1): 874
    DddA homolog search and engineering expand sequence compatibility of mitochondrial base editing.
    Li Mi, Ming Shi, Yu-Xuan Li, Gang Xie, Xichen Rao, Damu Wu, Aimin Cheng, Mengxiao Niu, Fengli Xu, Ying Yu, Ning Gao, Wensheng Wei, Xianhua Wang, Yangming Wang.
      Expanding mitochondrial base editing tools with broad sequence compatibility is of high need for both research and therapeutic purposes. In this study, we identify a DddA homolog from Simiaoa sunii (Ddd_Ss) which can efficiently deaminate cytosine in DC context in double-stranded DNA (dsDNA). We successfully develop Ddd_Ss-derived cytosine base editors (DdCBE_Ss) and introduce mutations at multiple mitochondrial DNA (mtDNA) loci including disease-associated mtDNA mutations in previously inaccessible GC context. Finally, by introducing a single amino acid substitution from Ddd_Ss, we successfully improve the activity and sequence compatibility of DdCBE derived from DddA of Burkholderia cenocepacia (DdCBE_Bc). Our study expands mtDNA editing tool boxes and provides resources for further screening and engineering dsDNA base editors for biological and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41467-023-36600-2
  7. Science. 2023 Feb 17. 379(6633): 655
    Decoding foreign antigen tolerance.
    Roser Vento-Tormo.
      Cell atlases of human tolerogenic milieus guide transformative immunotherapies.
    DOI:  https://doi.org/10.1126/science.adg6260
  8. Nat Commun. 2023 Feb 16. 14(1): 878
    Directed self-assembly of a xenogeneic vascularized endocrine pancreas for type 1 diabetes.
    Antonio Citro, Alessia Neroni, Cataldo Pignatelli, Francesco Campo, Martina Policardi, Matteo Monieri, Silvia Pellegrini, Erica Dugnani, Fabio Manenti, Maria Chiara Maffia, Libera Valla, Elisabeth Kemter, Ilaria Marzinotto, Cristina Olgasi, Alessia Cucci, Antonia Follenzi, Vito Lampasona, Eckhard Wolf, Lorenzo Piemonti.
      Intrahepatic islet transplantation is the standard cell therapy for β cell replacement. However, the shortage of organ donors and an unsatisfactory engraftment limit its application to a selected patients with type 1 diabetes. There is an urgent need to identify alternative strategies based on an unlimited source of insulin producing cells and innovative scaffolds to foster cell interaction and integration to orchestrate physiological endocrine function. We previously proposed the use of decellularized lung as a scaffold for β cell replacement with the final goal of engineering a vascularized endocrine organ. Here, we prototyped this technology with the integration of neonatal porcine islet and healthy subject-derived blood outgrowth endothelial cells to engineer a xenogeneic vascularized endocrine pancreas. We validated ex vivo cell integration and function, its engraftment and performance in a preclinical model of diabetes. Results showed that this technology not only is able to foster neonatal pig islet maturation in vitro, but also to perform in vivo immediately upon transplantation and for over 18 weeks, compared to normal performance within 8 weeks in various state of the art preclinical models. Given the recent progress in donor pig genetic engineering, this technology may enable the assembly of immune-protected functional endocrine organs.
    DOI:  https://doi.org/10.1038/s41467-023-36582-1
  9. Nat Commun. 2023 Feb 16. 14(1): 890
    Structural basis for membrane attack complex inhibition by CD59.
    Emma C Couves, Scott Gardner, Tomas B Voisin, Jasmine K Bickel, Phillip J Stansfeld, Edward W Tate, Doryen Bubeck.
      CD59 is an abundant immuno-regulatory receptor that protects human cells from damage during complement activation. Here we show how the receptor binds complement proteins C8 and C9 at the membrane to prevent insertion and polymerization of membrane attack complex (MAC) pores. We present cryo-electron microscopy structures of two inhibited MAC precursors known as C5b8 and C5b9. We discover that in both complexes, CD59 binds the pore-forming β-hairpins of C8 to form an intermolecular β-sheet that prevents membrane perforation. While bound to C8, CD59 deflects the cascading C9 β-hairpins, rerouting their trajectory into the membrane. Preventing insertion of C9 restricts structural transitions of subsequent monomers and indirectly halts MAC polymerization. We combine our structural data with cellular assays and molecular dynamics simulations to explain how the membrane environment impacts the dual roles of CD59 in controlling pore formation of MAC, and as a target of bacterial virulence factors which hijack CD59 to lyse human cells.
    DOI:  https://doi.org/10.1038/s41467-023-36441-z
  10. Nat Commun. 2023 Feb 15. 14(1): 850
    SVEP1 is an endogenous ligand for the orphan receptor PEAR1.
    Jared S Elenbaas, Upasana Pudupakkam, Katrina J Ashworth, Chul Joo Kang, Ved Patel, Katherine Santana, In-Hyuk Jung, Paul C Lee, Kendall H Burks, Junedh M Amrute, Robert P Mecham, Carmen M Halabi, Arturo Aliso, Jorge Di Paola, Nathan O Stitziel.
      Sushi, von Willebrand factor type A, EGF and pentraxin domain containing 1 (SVEP1) is an extracellular matrix protein that causally promotes vascular disease and associates with platelet reactivity in humans. Here, using a human genomic and proteomic approach, we identify a high affinity, disease-relevant, and potentially targetable interaction between SVEP1 and the orphan receptor Platelet and Endothelial Aggregation Receptor 1 (PEAR1). This interaction promotes PEAR1 phosphorylation and disease associated AKT/mTOR signaling in vascular cells and platelets. Mice lacking SVEP1 have reduced platelet activation, and exogenous SVEP1 induces PEAR1-dependent activation of platelets. SVEP1 and PEAR1 causally and concordantly relate to platelet phenotypes and cardiovascular disease in humans, as determined by Mendelian Randomization. Targeting this receptor-ligand interaction may be a viable therapeutic strategy to treat or prevent cardiovascular and thrombotic disease.
    DOI:  https://doi.org/10.1038/s41467-023-36486-0
  11. Immunity. 2023 Feb 07. pii: S1074-7613(23)00026-2. [Epub ahead of print]
    Infection induces tissue-resident memory NK cells that safeguard tissue health.
    Iona S Schuster, Xavier Y X Sng, Colleen M Lau, David R Powell, Orr-El Weizman, Peter Fleming, Georgia E G Neate, Valentina Voigt, Sam Sheppard, Andreas I Maraskovsky, Sheridan Daly, Motoko Koyama, Geoffrey R Hill, Stephen J Turner, Timothy E O'Sullivan, Joseph C Sun, Christopher E Andoniou, Mariapia A Degli-Esposti.
      Tissue health is dictated by the capacity to respond to perturbations and then return to homeostasis. Mechanisms that initiate, maintain, and regulate immune responses in tissues are therefore essential. Adaptive immunity plays a key role in these responses, with memory and tissue residency being cardinal features. A corresponding role for innate cells is unknown. Here, we have identified a population of innate lymphocytes that we term tissue-resident memory-like natural killer (NKRM) cells. In response to murine cytomegalovirus infection, we show that circulating NK cells were recruited in a CX3CR1-dependent manner to the salivary glands where they formed NKRM cells, a long-lived, tissue-resident population that prevented autoimmunity via TRAIL-dependent elimination of CD4+ T cells. Thus, NK cells develop adaptive-like features, including long-term residency in non-lymphoid tissues, to modulate inflammation, restore immune equilibrium, and preserve tissue health. Modulating the functions of NKRM cells may provide additional strategies to treat inflammatory and autoimmune diseases.
    Keywords:  CD4 T cells; Sjogren's syndrome; autoimmunity; cytomegalovirus; immune regulation; inflammation; memory; natural killer cells; tissue residency; viral infection
    DOI:  https://doi.org/10.1016/j.immuni.2023.01.016
  12. Nat Commun. 2023 Feb 16. 14(1): 873
    Deconstructing the modular organization and real-time dynamics of mammalian spinal locomotor networks.
    Li-Ju Hsu, Maëlle Bertho, Ole Kiehn.
      Locomotion empowers animals to move. Locomotor-initiating signals from the brain are funneled through descending neurons in the brainstem that act directly on spinal locomotor circuits. Little is known in mammals about which spinal circuits are targeted by the command and how this command is transformed into rhythmicity in the cord. Here we address these questions leveraging a mouse brainstem-spinal cord preparation from either sex that allows locating the locomotor command neurons with simultaneous Ca2+ imaging of spinal neurons. We show that a restricted brainstem area - encompassing the lateral paragigantocellular nucleus (LPGi) and caudal ventrolateral reticular nucleus (CVL) - contains glutamatergic neurons which directly initiate locomotion. Ca2+ imaging captures the direct LPGi/CVL locomotor initiating command in the spinal cord and visualizes spinal glutamatergic modules that execute the descending command and its transformation into rhythmic locomotor activity. Inhibitory spinal networks are recruited in a distinctly different pattern. Our study uncovers the principal logic of how spinal circuits implement the locomotor command using a distinct modular organization.
    DOI:  https://doi.org/10.1038/s41467-023-36587-w
  13. Nat Biotechnol. 2023 Feb 16.
    TACCO unifies annotation transfer and decomposition of cell identities for single-cell and spatial omics.
    Simon Mages, Noa Moriel, Inbal Avraham-Davidi, Evan Murray, Jan Watter, Fei Chen, Orit Rozenblatt-Rosen, Johanna Klughammer, Aviv Regev, Mor Nitzan.
      Transferring annotations of single-cell-, spatial- and multi-omics data is often challenging owing both to technical limitations, such as low spatial resolution or high dropout fraction, and to biological variations, such as continuous spectra of cell states. Based on the concept that these data are often best described as continuous mixtures of cells or molecules, we present a computational framework for the transfer of annotations to cells and their combinations (TACCO), which consists of an optimal transport model extended with different wrappers to annotate a wide variety of data. We apply TACCO to identify cell types and states, decipher spatiomolecular tissue structure at the cell and molecular level and resolve differentiation trajectories using synthetic and biological datasets. While matching or exceeding the accuracy of specialized tools for the individual tasks, TACCO reduces the computational requirements by up to an order of magnitude and scales to larger datasets (for example, considering the runtime of annotation transfer for 1 M simulated dropout observations).
    DOI:  https://doi.org/10.1038/s41587-023-01657-3
  14. Nat Commun. 2023 Feb 13. 14(1): 798
    Cross-protective antibodies against common endemic respiratory viruses.
    Madelyn Cabán, Justas V Rodarte, Madeleine Bibby, Matthew D Gray, Justin J Taylor, Marie Pancera, Jim Boonyaratanakornkit.
      Respiratory syncytial virus (RSV), human metapneumovirus (HMPV), and human parainfluenza virus types one (HPIV1) and three (HPIV3) can cause severe disease and death in immunocompromised patients, the elderly, and those with underlying lung disease. A protective monoclonal antibody exists for RSV, but clinical use is limited to high-risk infant populations. Hence, therapeutic options for these viruses in vulnerable patient populations are currently limited. Here, we present the discovery, in vitro characterization, and in vivo efficacy testing of two cross-neutralizing monoclonal antibodies, one targeting both HPIV3 and HPIV1 and the other targeting both RSV and HMPV. The 3 × 1 antibody is capable of targeting multiple parainfluenza viruses; the MxR antibody shares features with other previously reported monoclonal antibodies that are capable of neutralizing both RSV and HMPV. We obtained structures using cryo-electron microscopy of these antibodies in complex with their antigens at 3.62 Å resolution for 3 × 1 bound to HPIV3 and at 2.24 Å for MxR bound to RSV, providing a structural basis for in vitro binding and neutralization. Together, a cocktail of 3 × 1 and MxR could have clinical utility in providing broad protection against four of the respiratory viruses that cause significant morbidity and mortality in at-risk individuals.
    DOI:  https://doi.org/10.1038/s41467-023-36459-3
  15. Nat Commun. 2023 Feb 11. 14(1): 787
    The ubiquitination landscape of the influenza A virus polymerase.
    Franziska Günl, Tim Krischuns, Julian A Schreiber, Lea Henschel, Marius Wahrenburg, Hannes C A Drexler, Sebastian A Leidel, Vlad Cojocaru, Guiscard Seebohm, Alexander Mellmann, Martin Schwemmle, Stephan Ludwig, Linda Brunotte.
      During influenza A virus (IAV) infections, viral proteins are targeted by cellular E3 ligases for modification with ubiquitin. Here, we decipher and functionally explore the ubiquitination landscape of the IAV polymerase proteins during infection of human alveolar epithelial cells by applying mass spectrometry analysis of immuno-purified K-ε-GG (di-glycyl)-remnant-bearing peptides. We have identified 59 modified lysines across the three subunits, PB2, PB1 and PA of the viral polymerase of which 17 distinctively affect mRNA transcription, vRNA replication and the generation of recombinant viruses via non-proteolytic mechanisms. Moreover, further functional and in silico analysis indicate that ubiquitination at K578 in the PB1 thumb domain is mechanistically linked to dynamic structural transitions of the viral polymerase that are required for vRNA replication. Mutations K578A and K578R differentially affect the generation of recombinant viruses by impeding cRNA and vRNA synthesis, NP binding as well as polymerase dimerization. Collectively, our results demonstrate that the ubiquitin-mediated charge neutralization at PB1-K578 disrupts the interaction to an unstructured loop in the PB2 N-terminus that is required to coordinate polymerase dimerization and facilitate vRNA replication. This provides evidence that IAV exploits the cellular ubiquitin system to modulate the activity of the viral polymerase for viral replication.
    DOI:  https://doi.org/10.1038/s41467-023-36389-0
  16. Nat Commun. 2023 Feb 13. 14(1): 802
    Single-cell RNA-sequencing identifies disease-associated oligodendrocytes in male APP NL-G-F and 5XFAD mice.
    Hanseul Park, Byounggook Cho, Hongwon Kim, Takashi Saito, Takaomi C Saido, Kyoung-Jae Won, Jongpil Kim.
      Alzheimer's disease (AD) is associated with progressive neuronal degeneration as amyloid-beta (Aβ) and tau proteins accumulate in the brain. Glial cells were recently reported to play an important role in the development of AD. However, little is known about the role of oligodendrocytes in AD pathogenesis. Here, we describe a disease-associated subpopulation of oligodendrocytes that is present during progression of AD-like pathology in the male AppNL-G-F and male 5xFAD AD mouse brains and in postmortem AD human brains using single-cell RNA sequencing analysis. Aberrant Erk1/2 signaling was found to be associated with the activation of disease-associated oligodendrocytes (DAOs) in male AppNL-G-F mouse brains. Notably, inhibition of Erk1/2 signaling in DAOs rescued impaired axonal myelination and ameliorated Aβ-associated pathologies and cognitive decline in the male AppNL-G-F AD mouse model.
    DOI:  https://doi.org/10.1038/s41467-023-36519-8
  17. Nat Commun. 2023 Feb 16. 14(1): 871
    A trans-kingdom T6SS effector induces the fragmentation of the mitochondrial network and activates innate immune receptor NLRX1 to promote infection.
    Joana Sá-Pessoa, Sara López-Montesino, Kornelia Przybyszewska, Isabel Rodríguez-Escudero, Helina Marshall, Adelia Ova, Gunnar N Schroeder, Peter Barabas, María Molina, Tim Curtis, Víctor J Cid, José A Bengoechea.
      Bacteria can inhibit the growth of other bacteria by injecting effectors using a type VI secretion system (T6SS). T6SS effectors can also be injected into eukaryotic cells to facilitate bacterial survival, often by targeting the cytoskeleton. Here, we show that the trans-kingdom antimicrobial T6SS effector VgrG4 from Klebsiella pneumoniae triggers the fragmentation of the mitochondrial network. VgrG4 colocalizes with the endoplasmic reticulum (ER) protein mitofusin 2. VgrG4 induces the transfer of Ca2+ from the ER to the mitochondria, activating Drp1 (a regulator of mitochondrial fission) thus leading to mitochondrial network fragmentation. Ca2+ elevation also induces the activation of the innate immunity receptor NLRX1 to produce reactive oxygen species (ROS). NLRX1-induced ROS limits NF-κB activation by modulating the degradation of the NF-κB inhibitor IκBα. The degradation of IκBα is triggered by the ubiquitin ligase SCFβ-TrCP, which requires the modification of the cullin-1 subunit by NEDD8. VgrG4 abrogates the NEDDylation of cullin-1 by inactivation of Ubc12, the NEDD8-conjugating enzyme. Our work provides an example of T6SS manipulation of eukaryotic cells via alteration of the mitochondria.
    DOI:  https://doi.org/10.1038/s41467-023-36629-3
  18. Sci Adv. 2023 Feb 17. 9(7): eabo1360
    Multiscale 3D genome reorganization during skeletal muscle stem cell lineage progression and aging.
    Yu Zhao, Yingzhe Ding, Liangqiang He, Qin Zhou, Xiaona Chen, Yuying Li, Maria Vittoria Alfonsi, Zhenguo Wu, Hao Sun, Huating Wang.
      Little is known about three-dimensional (3D) genome organization in skeletal muscle stem cells [also called satellite cells (SCs)]. Here, we comprehensively map the 3D genome topology reorganization during mouse SC lineage progression. Specifically, rewiring at the compartment level is most pronounced when SCs become activated. Marked loss in topologically associating domain (TAD) border insulation and chromatin looping also occurs during early activation process. Meanwhile, TADs can form TAD clusters and super-enhancer-containing TAD clusters orchestrate stage-specific gene expression. Furthermore, we uncover that transcription factor PAX7 is pivotal in enhancer-promoter (E-P) loop formation. We also identify cis-regulatory elements that are crucial for local chromatin organization at Pax7 locus and Pax7 expression. Lastly, we unveil that geriatric SC displays a prominent gain in long-range contacts and loss of TAD border insulation. Together, our results uncover that 3D chromatin extensively reorganizes at multiple architectural levels and underpins the transcriptome remodeling during SC lineage development and SC aging.
    DOI:  https://doi.org/10.1126/sciadv.abo1360
  19. Nat Protoc. 2023 Feb 15.
    Mitochondrial single-cell ATAC-seq for high-throughput multi-omic detection of mitochondrial genotypes and chromatin accessibility.
    Caleb A Lareau, Vincent Liu, Christoph Muus, Samantha D Praktiknjo, Lena Nitsch, Pauline Kautz, Katalin Sandor, Yajie Yin, Jacob C Gutierrez, Karin Pelka, Ansuman T Satpathy, Aviv Regev, Vijay G Sankaran, Leif S Ludwig.
      Natural sequence variation within mitochondrial DNA (mtDNA) contributes to human phenotypes and may serve as natural genetic markers in human cells for clonal and lineage tracing. We recently developed a single-cell multi-omic approach, called 'mitochondrial single-cell assay for transposase-accessible chromatin with sequencing' (mtscATAC-seq), enabling concomitant high-throughput mtDNA genotyping and accessible chromatin profiling. Specifically, our technique allows the mitochondrial genome-wide inference of mtDNA variant heteroplasmy along with information on cell state and accessible chromatin variation in individual cells. Leveraging somatic mtDNA mutations, our method further enables inference of clonal relationships among native ex vivo-derived human cells not amenable to genetic engineering-based clonal tracing approaches. Here, we provide a step-by-step protocol for the use of mtscATAC-seq, including various cell-processing and flow cytometry workflows, by using primary hematopoietic cells, subsequent single-cell genomic library preparation and sequencing that collectively take ~3-4 days to complete. We discuss experimental and computational data quality control metrics and considerations for the extension to other mammalian tissues. Overall, mtscATAC-seq provides a broadly applicable platform to map clonal relationships between cells in human tissues, investigate fundamental aspects of mitochondrial genetics and enable additional modes of multi-omic discovery.
    DOI:  https://doi.org/10.1038/s41596-022-00795-3
  20. Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2209177120
    Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer's disease.
    Lauren H Fairley, Kei Onn Lai, Jia Hui Wong, Wei Jing Chong, Anselm Salvatore Vincent, Giuseppe D'Agostino, Xiaoting Wu, Roshan R Naik, Anusha Jayaraman, Sarah R Langley, Christiane Ruedl, Anna M Barron.
      Microglial phagocytosis is an energetically demanding process that plays a critical role in the removal of toxic protein aggregates in Alzheimer's disease (AD). Recent evidence indicates that a switch in energy production from mitochondrial respiration to glycolysis disrupts this important protective microglial function and may provide therapeutic targets for AD. Here, we demonstrate that the translocator protein (TSPO) and a member of its mitochondrial complex, hexokinase-2 (HK), play critical roles in microglial respiratory-glycolytic metabolism and phagocytosis. Pharmacological and genetic loss-of-function experiments showed that TSPO is critical for microglial respiratory metabolism and energy supply for phagocytosis, and its expression is enriched in phagocytic microglia of AD mice. Meanwhile, HK controlled glycolytic metabolism and phagocytosis via mitochondrial binding or displacement. In cultured microglia, TSPO deletion impaired mitochondrial respiration and increased mitochondrial recruitment of HK, inducing a switch to glycolysis and reducing phagocytosis. To determine the functional significance of mitochondrial HK recruitment, we developed an optogenetic tool for reversible control of HK localization. Displacement of mitochondrial HK inhibited glycolysis and improved phagocytosis in TSPO-knockout microglia. Mitochondrial HK recruitment also coordinated the inflammatory switch to glycolysis that occurs in response to lipopolysaccharide in normal microglia. Interestingly, cytosolic HK increased phagocytosis independent of its metabolic activity, indicating an immune signaling function. Alzheimer's beta amyloid drastically stimulated mitochondrial HK recruitment in cultured microglia, which may contribute to microglial dysfunction in AD. Thus, targeting mitochondrial HK may offer an immunotherapeutic approach to promote phagocytic microglial function in AD.
    Keywords:  Alzheimer’s disease; hexokinase; immunometabolism; mitochondria; translocator protein
    DOI:  https://doi.org/10.1073/pnas.2209177120
  21. Nat Biotechnol. 2023 Feb 13.
    gutSMASH predicts specialized primary metabolic pathways from the human gut microbiota.
    Victòria Pascal Andreu, Hannah E Augustijn, Lianmin Chen, Alexandra Zhernakova, Jingyuan Fu, Michael A Fischbach, Dylan Dodd, Marnix H Medema.
      The gut microbiota produce hundreds of small molecules, many of which modulate host physiology. Although efforts have been made to identify biosynthetic genes for secondary metabolites, the chemical output of the gut microbiome consists predominantly of primary metabolites. Here we introduce the gutSMASH algorithm for identification of primary metabolic gene clusters, and we used it to systematically profile gut microbiome metabolism, identifying 19,890 gene clusters in 4,240 high-quality microbial genomes. We found marked differences in pathway distribution among phyla, reflecting distinct strategies for energy capture. These data explain taxonomic differences in short-chain fatty acid production and suggest a characteristic metabolic niche for each taxon. Analysis of 1,135 individuals from a Dutch population-based cohort shows that the level of microbiome-derived metabolites in plasma and feces is almost completely uncorrelated with the metagenomic abundance of corresponding metabolic genes, indicating a crucial role for pathway-specific gene regulation and metabolite flux. This work is a starting point for understanding differences in how bacterial taxa contribute to the chemistry of the microbiome.
    DOI:  https://doi.org/10.1038/s41587-023-01675-1
  22. EMBO Rep. 2023 Feb 16. e55548
    Reverse electron transfer is activated during aging and contributes to aging and age-related disease.
    Suman Rimal, Ishaq Tantray, Yu Li, Tejinder Pal Khaket, Yanping Li, Sunil Bhurtel, Wen Li, Cici Zeng, Bingwei Lu.
      Mechanisms underlying the depletion of NAD+ and accumulation of reactive oxygen species (ROS) in aging and age-related disorders remain poorly defined. We show that reverse electron transfer (RET) at mitochondrial complex I, which causes increased ROS production and NAD+ to NADH conversion and thus lowered NAD+ /NADH ratio, is active during aging. Genetic or pharmacological inhibition of RET decreases ROS production and increases NAD+ /NADH ratio, extending the lifespan of normal flies. The lifespan-extending effect of RET inhibition is dependent on NAD+ -dependent Sirtuin, highlighting the importance of NAD+ /NADH rebalance, and on longevity-associated Foxo and autophagy pathways. RET and RET-induced ROS and NAD+ /NADH ratio changes are prominent in human induced pluripotent stem cell (iPSC) model and fly models of Alzheimer's disease (AD). Genetic or pharmacological inhibition of RET prevents the accumulation of faulty translation products resulting from inadequate ribosome-mediated quality control, rescues relevant disease phenotypes, and extends the lifespan of Drosophila and mouse AD models. Deregulated RET is therefore a conserved feature of aging, and inhibition of RET may open new therapeutic opportunities in the context of aging and age-related diseases including AD.
    Keywords:  Alzheimer's disease; NAD+/NADH ratio; lifespan; mitochondrial complex I; reverse electron transport
    DOI:  https://doi.org/10.15252/embr.202255548
  23. Diabetes Care. 2023 Feb 14. pii: dc221954. [Epub ahead of print]
    Association and Interaction of Genetics and Area-Level Socioeconomic Factors on the Prevalence of Type 2 Diabetes and Obesity.
    Sara J Cromer, Chirag M Lakhani, Josep M Mercader, Timothy D Majarian, Philip Schroeder, Joanne B Cole, Jose C Florez, Chirag J Patel, Alisa K Manning, Sherri-Ann M Burnett-Bowie, Jordi Merino, Miriam S Udler.
       OBJECTIVE: Quantify the impact of genetic and socioeconomic factors on risk of type 2 diabetes (T2D) and obesity.
    RESEARCH DESIGN AND METHODS: Among participants in the Mass General Brigham Biobank (MGBB) and UK Biobank (UKB), we used logistic regression models to calculate cross-sectional odds of T2D and obesity using 1) polygenic risk scores for T2D and BMI and 2) area-level socioeconomic risk (educational attainment) measures. The primary analysis included 26,737 participants of European genetic ancestry in MGBB with replication in UKB (N = 223,843), as well as in participants of non-European ancestry (MGBB N = 3,468; UKB N = 7,459).
    RESULTS: The area-level socioeconomic measure most strongly associated with both T2D and obesity was percent without a college degree, and associations with disease prevalence were independent of genetic risk (P < 0.001 for each). Moving from lowest to highest quintiles of combined genetic and socioeconomic burden more than tripled T2D (3.1% to 22.2%) and obesity (20.9% to 69.0%) prevalence. Favorable socioeconomic risk was associated with lower disease prevalence, even in those with highest genetic risk (T2D 13.0% vs. 22.2%, obesity 53.6% vs. 69.0% in lowest vs. highest socioeconomic risk quintiles). Additive effects of genetic and socioeconomic factors accounted for 13.2% and 16.7% of T2D and obesity prevalence, respectively, explained by these models. Findings were replicated in independent European and non-European ancestral populations.
    CONCLUSIONS: Genetic and socioeconomic factors significantly interact to increase risk of T2D and obesity. Favorable area-level socioeconomic status was associated with an almost 50% lower T2D prevalence in those with high genetic risk.
    DOI:  https://doi.org/10.2337/dc22-1954
  24. Nat Commun. 2023 Feb 16. 14(1): 895
    Network of hotspot interactions cluster tau amyloid folds.
    Vishruth Mullapudi, Jaime Vaquer-Alicea, Vaibhav Bommareddy, Anthony R Vega, Bryan D Ryder, Charles L White, Marc I Diamond, Lukasz A Joachimiak.
      Cryogenic electron microscopy has revealed unprecedented molecular insight into the conformations of β-sheet-rich protein amyloids linked to neurodegenerative diseases. It remains unknown how a protein can adopt a diversity of folds and form multiple distinct fibrillar structures. Here we develop an in silico alanine scan method to estimate the relative energetic contribution of each amino acid in an amyloid assembly. We apply our method to twenty-seven ex vivo and in vitro fibril structural polymorphs of the microtubule-associated protein tau. We uncover networks of energetically important interactions involving amyloid-forming motifs that stabilize the different fibril folds. We evaluate our predictions in cellular and in vitro aggregation assays. Using a machine learning approach, we classify the structures based on residue energetics to identify distinguishing and unifying features. Our energetic profiling suggests that minimal sequence elements control the stability of tau fibrils, allowing future design of protein sequences that fold into unique structures.
    DOI:  https://doi.org/10.1038/s41467-023-36572-3
  25. Nature. 2023 Feb 15.
    'Mirror neurons' fire up during mouse battles.
    Max Kozlov.
      
    Keywords:  Neuroscience
    DOI:  https://doi.org/10.1038/d41586-023-00418-1
  26. Cell Stem Cell. 2023 Feb 07. pii: S1934-5909(23)00009-7. [Epub ahead of print]
    Kupffer-cell-derived IL-6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury-specific enhancers.
    Lu Li, Lei Cui, Ping Lin, Zhaoyuan Liu, Shujie Bao, Xiaolong Ma, Haitao Nan, Wencheng Zhu, Jin Cen, Yunuo Mao, Xiong Ma, Lingyong Jiang, Yu Nie, Florent Ginhoux, Yixue Li, Hong Li, Lijian Hui.
      Stem cell-independent reprogramming of differentiated cells has recently been identified as an important paradigm for repairing injured tissues. Following periportal injury, mature hepatocytes re-activate reprogramming/progenitor-related genes (RRGs) and dedifferentiate into liver progenitor-like cells (LPLCs) in both mice and humans, which contribute remarkably to regeneration. However, it remains unknown which and how external factors trigger hepatocyte reprogramming. Here, by employing single-cell transcriptional profiling and lineage-specific deletion tools, we uncovered that periportal-specific LPLC formation was initiated by regionally activated Kupffer cells but not peripheral monocyte-derived macrophages. Unexpectedly, using in vivo screening, the proinflammatory factor IL-6 was identified as the niche signal repurposed for RRG induction via STAT3 activation, which drove RRG expression through binding to their pre-accessible enhancers. Notably, RRGs were activated through injury-specific rather than liver embryogenesis-related enhancers. Collectively, these findings depict an injury-specific niche signal and the inflammation-mediated transcription in driving the conversion of hepatocytes into a progenitor phenotype.
    Keywords:  IL-6/STAT3 signaling; Kupffer cells; hepatocyte reprogramming; liver repair; transcriptional regulation of reprogramming/progenitor-related genes
    DOI:  https://doi.org/10.1016/j.stem.2023.01.009
  27. Science. 2023 Feb 17. 379(6633): eabg2752
    CD5 expression by dendritic cells directs T cell immunity and sustains immunotherapy responses.
    Mingyu He, Kate Roussak, Feiyang Ma, Nicholas Borcherding, Vince Garin, Mike White, Charles Schutt, Trine I Jensen, Yun Zhao, Courtney A Iberg, Kairav Shah, Himanshi Bhatia, Daniel Korenfeld, Sabrina Dinkel, Judah Gray, Alina Ulezko Antonova, Stephen Ferris, David Donermeyer, Cecilia Lindestam Arlehamn, Matthew M Gubin, Jingqin Luo, Laurent Gorvel, Matteo Pellegrini, Alessandro Sette, Thomas Tung, Rasmus Bak, Robert L Modlin, Ryan C Fields, Robert D Schreiber, Paul M Allen, Eynav Klechevsky.
      The induction of proinflammatory T cells by dendritic cell (DC) subtypes is critical for antitumor responses and effective immune checkpoint blockade (ICB) therapy. Here, we show that human CD1c+CD5+ DCs are reduced in melanoma-affected lymph nodes, with CD5 expression on DCs correlating with patient survival. Activating CD5 on DCs enhanced T cell priming and improved survival after ICB therapy. CD5+ DC numbers increased during ICB therapy, and low interleukin-6 (IL-6) concentrations promoted their de novo differentiation. Mechanistically, CD5 expression by DCs was required to generate optimally protective CD5hi T helper and CD8+ T cells; further, deletion of CD5 from T cells dampened tumor elimination in response to ICB therapy in vivo. Thus, CD5+ DCs are an essential component of optimal ICB therapy.
    DOI:  https://doi.org/10.1126/science.abg2752
  28. Nat Commun. 2023 Feb 16. 14(1): 872
    Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus.
    Naijun Miao, Zhuning Wang, Qinlan Wang, Hongyan Xie, Ninghao Yang, Yanzhe Wang, Jin Wang, Haixia Kang, Wenjuan Bai, Yuanyuan Wang, Rui He, Kepeng Yan, Yang Wang, Qiongyi Hu, Zhaoyuan Liu, Fubin Li, Feng Wang, Florent Ginhoux, Xiaoling Zhang, Jianyong Yin, Limin Lu, Jing Wang.
      Although extracellular DNA is known to form immune complexes (ICs) with autoantibodies in systemic lupus erythematosus (SLE), the mechanisms leading to the release of DNA from cells remain poorly characterized. Here, we show that the pore-forming protein, gasdermin D (GSDMD), is required for nuclear DNA and mitochondrial DNA (mtDNA) release from neutrophils and lytic cell death following ex vivo stimulation with serum from patients with SLE and IFN-γ. Mechanistically, the activation of FcγR downregulated Serpinb1 following ex vivo stimulation with serum from patients with SLE, leading to spontaneous activation of both caspase-1/caspase-11 and cleavage of GSDMD into GSDMD-N. Furthermore, mtDNA oxidization promoted GSDMD-N oligomerization and cell death. In addition, GSDMD, but not peptidyl arginine deiminase 4 is necessary for extracellular mtDNA release from low-density granulocytes from SLE patients or healthy human neutrophils following incubation with ICs. Using the pristane-induced lupus model, we show that disease severity is significantly reduced in mice with neutrophil-specific Gsdmd deficiency or following treatment with the GSDMD inhibitor, disulfiram. Altogether, our study highlights an important role for oxidized mtDNA in inducing GSDMD oligomerization and pore formation. These findings also suggest that GSDMD might represent a possible therapeutic target in SLE.
    DOI:  https://doi.org/10.1038/s41467-023-36522-z
  29. Sci Transl Med. 2023 Feb 15. 15(683): eabj3289
    IRAK4 inhibition dampens pathogenic processes driving inflammatory skin diseases.
    Stéphanie Lavazais, Manja Jargosch, Sonia Dupont, Frédéric Labéguère, Christel Menet, Catherine Jagerschmidt, Frenz Ohm, Laszlo Kupcsik, Isabelle Parent, Céline Cottereaux, Florence Marsais, Line Oste, An Van de Water, Thierry Christophe, Steve De Vos, Padraic Fallon, Felix Lauffer, Philippe Clément-Lacroix, Kilian Eyerich, Reginald Brys.
      Innate immunity not only shapes the way epithelial barriers interpret environmental cues but also drives adaptive responses. Therefore, modulators of innate immune responses are expected to have high therapeutic potential across immune-mediated inflammatory diseases. IRAK4 is a kinase that integrates signaling downstream of receptors acting at the interface between innate and adaptive immune responses, such as Toll-like receptors (TLRs), interleukin-1R (IL-1R), and IL-18R. Because effects of IRAK4 inhibition are stimulus, cell type, and species dependent, the evaluation of the therapeutic potential of IRAK4 inhibitors requires a highly translational approach. Here, we profiled a selective IRAK4 inhibitor, GLPG2534, in an extensive panel of models of inflammatory skin diseases, translationally expanding evidence from in vitro to in vivo and from mouse to human. In vitro, IRAK4 inhibition resulted in substantial inhibition of TLR and IL-1 responses in dendritic cells, keratinocytes, granulocytes, and T cells but only weakly affected dermal fibroblast responses. Furthermore, disease activity in murine models of skin inflammation (IL-23-, IL-33-, imiquimod-, and MC903-induced) was markedly dampened by IRAK4 inhibition. Last, inhibiting IRAK4 reversed pathogenic molecular signatures in human lesional psoriasis and atopic dermatitis biopsies. Over the variety of models used, IRAK4 inhibition consistently affected central mediators of psoriasis (IL-17A) and atopic dermatitis (IL-4 and IL-13). Overall, our data highlight IRAK4 as a central player in skin inflammatory processes and demonstrate the potential of IRAK4 inhibition as a therapeutic strategy in chronic inflammatory skin diseases.
    DOI:  https://doi.org/10.1126/scitranslmed.abj3289
  30. Nat Commun. 2023 Feb 11. 14(1): 771
    T cell-independent eradication of experimental glioma by intravenous TLR7/8-agonist-loaded nanoparticles.
    Verena Turco, Kira Pfleiderer, Jessica Hunger, Natalie K Horvat, Kianush Karimian-Jazi, Katharina Schregel, Manuel Fischer, Gianluca Brugnara, Kristine Jähne, Volker Sturm, Yannik Streibel, Duy Nguyen, Sandro Altamura, Dennis A Agardy, Shreya S Soni, Abdulrahman Alsasa, Theresa Bunse, Matthias Schlesner, Martina U Muckenthaler, Ralph Weissleder, Wolfgang Wick, Sabine Heiland, Philipp Vollmuth, Martin Bendszus, Christopher B Rodell, Michael O Breckwoldt, Michael Platten.
      Glioblastoma, the most common and aggressive primary brain tumor type, is considered an immunologically "cold" tumor with sparse infiltration by adaptive immune cells. Immunosuppressive tumor-associated myeloid cells are drivers of tumor progression. Therefore, targeting and reprogramming intratumoral myeloid cells is an appealing therapeutic strategy. Here, we investigate a β-cyclodextrin nanoparticle (CDNP) formulation encapsulating the Toll-like receptor 7 and 8 (TLR7/8) agonist R848 (CDNP-R848) to reprogram myeloid cells in the glioma microenvironment. We show that intravenous monotherapy with CDNP-R848 induces regression of established syngeneic experimental glioma, resulting in increased survival rates compared with unloaded CDNP controls. Mechanistically, CDNP-R848 treatment reshapes the immunosuppressive tumor microenvironment and orchestrates tumor clearing by pro-inflammatory tumor-associated myeloid cells, independently of T cells and NK cells. Using serial magnetic resonance imaging, we identify a radiomic signature in response to CDNP-R848 treatment and ultrasmall superparamagnetic iron oxide (USPIO) imaging reveals that immunosuppressive macrophage recruitment is reduced by CDNP-R848. In conclusion, CDNP-R848 induces tumor regression in experimental glioma by targeting blood-borne macrophages without requiring adaptive immunity.
    DOI:  https://doi.org/10.1038/s41467-023-36321-6
  31. J Immunol. 2023 Feb 13. pii: ji2200785. [Epub ahead of print]
    IL-1/MyD88-Dependent G-CSF and IL-6 Secretion Mediates Postburn Anemia.
    John G Noel, Seth W Ramser, Lori Pitstick, Holly S Goetzman, Elizabeth L Dale, Andrew Potter, Mike Adam, S Steven Potter, Jason C Gardner.
      The anemia of critical illness (ACI) is a nearly universal pathophysiological consequence of burn injury and a primary reason burn patients require massive quantities of transfused blood. Inflammatory processes are expected to drive postburn ACI and prevent meaningful erythropoietic stimulation through iron or erythropoietin supplementation, but to this day no specific inflammatory pathways have been identified as a critical mechanism. In this study, we examined whether secretion of G-CSF and IL-6 mediates distinct features of postburn ACI and interrogated inflammatory mechanisms that could be responsible for their secretion. Our analysis of mouse and human skin samples identified the burn wound as a primary source of G-CSF and IL-6 secretion. We show that G-CSF and IL-6 are secreted independently through an IL-1/MyD88-dependent mechanism, and we ruled out TLR2 and TLR4 as critical receptors. Our results indicate that IL-1/MyD88-dependent G-CSF secretion plays a key role in impairing medullary erythropoiesis and IL-6 secretion plays a key role in limiting the access of erythroid cells to iron. Importantly, we found that IL-1α/β neutralizing Abs broadly attenuated features of postburn ACI that could be attributed to G-CSF or IL-6 secretion and rescued deficits of circulating RBC counts, hemoglobin, and hematocrit caused by burn injury. We conclude that wound-based IL-1/MyD88 signaling mediates postburn ACI through induction of G-CSF and IL-6 secretion.
    DOI:  https://doi.org/10.4049/jimmunol.2200785
  32. Cell Genom. 2022 Mar 09. 2(3): 100101
    Decoding the diversity of killer immunoglobulin-like receptors by deep sequencing and a high-resolution imputation method.
    Saori Sakaue, Kazuyoshi Hosomichi, Jun Hirata, Hirofumi Nakaoka, Keiko Yamazaki, Makoto Yawata, Nobuyo Yawata, Tatsuhiko Naito, Junji Umeno, Takaaki Kawaguchi, Toshiyuki Matsui, Satoshi Motoya, Yasuo Suzuki, Hidetoshi Inoko, Atsushi Tajima, Takayuki Morisaki, Koichi Matsuda, Yoichiro Kamatani, Kazuhiko Yamamoto, Ituro Inoue, Yukinori Okada.
      The killer cell immunoglobulin-like receptor (KIR) recognizes human leukocyte antigen (HLA) class I molecules and modulates the function of natural killer cells. Despite its role in immunity, the complex genomic structure has limited a deep understanding of the KIR genomic landscape. Here we conduct deep sequencing of 16 KIR genes in 1,173 individuals. We devise a bioinformatics pipeline incorporating copy number estimation and insertion or deletion (indel) calling for high-resolution KIR genotyping. We define 118 alleles in 13 genes and demonstrate a linkage disequilibrium structure within and across KIR centromeric and telomeric regions. We construct a KIR imputation reference panel (nreference = 689, imputation accuracy = 99.7%), apply it to biobank genotype (ntotal = 169,907), and perform phenome-wide association studies of 85 traits. We observe a dearth of genome-wide significant associations, even in immune traits implicated previously to be associated with KIR (the smallest p = 1.5 × 10-4). Our pipeline presents a broadly applicable framework to evaluate innate immunity in large-scale datasets.
    Keywords:  KIR; PheWAS; biobank; immunogenetics; imputation; killer cell immunoglobulin-like receptor; next-generation sequencing; target sequencing
    DOI:  https://doi.org/10.1016/j.xgen.2022.100101
  33. Nat Commun. 2023 Feb 13. 14(1): 721
    Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation.
    Stefania Crotta, Matteo Villa, Jack Major, Katja Finsterbusch, Miriam Llorian, Peter Carmeliet, Joerg Buescher, Andreas Wack.
      Epithelial tissues provide front-line barriers shielding the organism from invading pathogens and harmful substances. In the airway epithelium, the combined action of multiciliated and secretory cells sustains the mucociliary escalator required for clearance of microbes and particles from the airways. Defects in components of mucociliary clearance or barrier integrity are associated with recurring infections and chronic inflammation. The timely and balanced differentiation of basal cells into mature epithelial cell subsets is therefore tightly controlled. While different growth factors regulating progenitor cell proliferation have been described, little is known about the role of metabolism in these regenerative processes. Here we show that basal cell differentiation correlates with a shift in cellular metabolism from glycolysis to fatty acid oxidation (FAO). We demonstrate both in vitro and in vivo that pharmacological and genetic impairment of FAO blocks the development of fully differentiated airway epithelial cells, compromising the repair of airway epithelia. Mechanistically, FAO links to the hexosamine biosynthesis pathway to support protein glycosylation in airway epithelial cells. Our findings unveil the metabolic network underpinning the differentiation of airway epithelia and identify novel targets for intervention to promote lung repair.
    DOI:  https://doi.org/10.1038/s41467-023-36352-z
  34. Cell Genom. 2022 Dec 14. 2(12): 100214
    Type 1 diabetes risk genes mediate pancreatic beta cell survival in response to proinflammatory cytokines.
    Paola Benaglio, Han Zhu, Mei-Lin Okino, Jian Yan, Ruth Elgamal, Naoki Nariai, Elisha Beebe, Katha Korgaonkar, Yunjiang Qiu, Margaret K R Donovan, Joshua Chiou, Gaowei Wang, Jacklyn Newsome, Jaspreet Kaur, Michael Miller, Sebastian Preissl, Sierra Corban, Anthony Aylward, Jussi Taipale, Bing Ren, Kelly A Frazer, Maike Sander, Kyle J Gaulton.
      We combined functional genomics and human genetics to investigate processes that affect type 1 diabetes (T1D) risk by mediating beta cell survival in response to proinflammatory cytokines. We mapped 38,931 cytokine-responsive candidate cis-regulatory elements (cCREs) in beta cells using ATAC-seq and snATAC-seq and linked them to target genes using co-accessibility and HiChIP. Using a genome-wide CRISPR screen in EndoC-βH1 cells, we identified 867 genes affecting cytokine-induced survival, and genes promoting survival and up-regulated in cytokines were enriched at T1D risk loci. Using SNP-SELEX, we identified 2,229 variants in cytokine-responsive cCREs altering transcription factor (TF) binding, and variants altering binding of TFs regulating stress, inflammation, and apoptosis were enriched for T1D risk. At the 16p13 locus, a fine-mapped T1D variant altering TF binding in a cytokine-induced cCRE interacted with SOCS1, which promoted survival in cytokine exposure. Our findings reveal processes and genes acting in beta cells during inflammation that modulate T1D risk.
    Keywords:  3D chromatin interactions; CRISPR screen; accessible chromatin; beta cell; functional genomics; gene expression; high-throughput reporter assay; human genetics; proinflammatory cytokines; type 1 diabetes
    DOI:  https://doi.org/10.1016/j.xgen.2022.100214
  35. Immunity. 2023 Feb 14. pii: S1074-7613(23)00033-X. [Epub ahead of print]56(2): 237-239
    Fragile-like regulatory T cells modulate opioid withdrawal in humans and mice.
    Marwa O Mikati, Robyn S Klein.
      Opioid use alters peripheral immune functions via unknown mechanisms. In a recent issue of Cell, Zhu et al. report increased fragile-like regulatory T cells in patients with opioid use disorder and in morphine-treated mice. In mice, Treg cell-derived interferon-γ within the brain promotes withdrawal-associated alterations in synapses.
    DOI:  https://doi.org/10.1016/j.immuni.2023.01.021
  36. Nat Med. 2023 Feb 16.
    Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice.
    Daniel Reichart, Gregory A Newby, Hiroko Wakimoto, Mingyue Lun, Joshua M Gorham, Justin J Curran, Aditya Raguram, Daniel M DeLaughter, David A Conner, Júlia D C Marsiglia, Sajeev Kohli, Lukas Chmatal, David C Page, Nerea Zabaleta, Luk Vandenberghe, David R Liu, Jonathan G Seidman, Christine Seidman.
      Dominant missense pathogenic variants in cardiac myosin heavy chain cause hypertrophic cardiomyopathy (HCM), a currently incurable disorder that increases risk for stroke, heart failure and sudden cardiac death. In this study, we assessed two different genetic therapies-an adenine base editor (ABE8e) and a potent Cas9 nuclease delivered by AAV9-to prevent disease in mice carrying the heterozygous HCM pathogenic variant myosin R403Q. One dose of dual-AAV9 vectors, each carrying one half of RNA-guided ABE8e, corrected the pathogenic variant in ≥70% of ventricular cardiomyocytes and maintained durable, normal cardiac structure and function. An additional dose provided more editing in the atria but also increased bystander editing. AAV9 delivery of RNA-guided Cas9 nuclease effectively inactivated the pathogenic allele, albeit with dose-dependent toxicities, necessitating a narrow therapeutic window to maintain health. These preclinical studies demonstrate considerable potential for single-dose genetic therapies to correct or silence pathogenic variants and prevent the development of HCM.
    DOI:  https://doi.org/10.1038/s41591-022-02190-7
  37. Cell Genom. 2022 Dec 14. 2(12): 100212
    Multi-ancestry meta-analysis of asthma identifies novel associations and highlights the value of increased power and diversity.
    Global Biobank Meta-analysis Initiative
      Asthma is a complex disease that varies widely in prevalence across populations. The extent to which genetic variation contributes to these disparities is unclear, as the genetics underlying asthma have been investigated primarily in populations of European descent. As part of the Global Biobank Meta-analysis Initiative, we conducted a large-scale genome-wide association study of asthma (153,763 cases and 1,647,022 controls) via meta-analysis across 22 biobanks spanning multiple ancestries. We discovered 179 asthma-associated loci, 49 of which were not previously reported. Despite the wide range in asthma prevalence among biobanks, we found largely consistent genetic effects across biobanks and ancestries. The meta-analysis also improved polygenic risk prediction in non-European populations compared with previous studies. Additionally, we found considerable genetic overlap between age-of-onset subtypes and between asthma and comorbid diseases. Our work underscores the multi-factorial nature of asthma development and offers insight into its shared genetic architecture.
    Keywords:  GWAS; asthma; cross-trait; heterogeneity; meta-analysis; multi-ancestry; polygenic risk prediction; subtypes
    DOI:  https://doi.org/10.1016/j.xgen.2022.100212
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