bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024‒02‒04
forty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Health in Africa.
  2. Baby in tow.
  3. Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis.
  4. Stress response silencing by an E3 ligase mutated in neurodegeneration.
  5. Tissue-specific profiling of age-dependent miRNAomic changes in Caenorhabditis elegans.
  6. Neutrophil surface RNAs promote entry to inflamed sites.
  7. Arterial pulses link heart-brain oscillations.
  8. CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses.
  9. Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates.
  10. Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity.
  11. Rescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics.
  12. Throwing IL-1β for a loop.
  13. Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.
  14. An epigenetic barrier sets the timing of human neuronal maturation.
  15. Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2.
  16. Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision.
  17. Xist ribonucleoproteins promote female sex-biased autoimmunity.
  18. KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.
  19. A lncRNA Dleu2-encoded peptide relieves autoimmunity by facilitating Smad3-mediated Treg induction.
  20. Natural inhibitor found for cell death by ferroptosis.
  21. Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis.
  22. Promoting (and targeting) alternative expression.
  23. GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.
  24. Why human brain cells grow so slowly.
  25. Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages.
  26. Mapping brain-immune interactions in ischemic stroke.
  27. Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.
  28. The immunology of type 1 diabetes.
  29. Effect of aging on the human myometrium at single-cell resolution.
  30. Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.
  31. Age-related motor deficits caused by clonal haematopoiesis-driven, monocyte-derived microglia.
  32. Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress.
  33. Rescue of mitochondrial import failure by intercellular organellar transfer.
  34. Humoral profiles of toddlers and young children following SARS-CoV-2 mRNA vaccination.
  35. Single-neuronal elements of speech production in humans.
  36. TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue.
  37. Ultra-fast label-free quantification and comprehensive proteome coverage with narrow-window data-independent acquisition.
  38. Mechanical forces across compartments coordinate cell shape and fate transitions to generate tissue architecture.
  39. A 25-year odyssey of genomic technology advances and structural variant discovery.
  40. Snapshots of genetic copy-and-paste machinery in action.
  41. H3K27M neoepitope vaccination in diffuse midline glioma induces B and T cell responses across diverse HLA loci of a recovered patient.
  42. Semi-supervised integration of single-cell transcriptomics data.
  43. Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.
  44. Unraveling the Tcrb interactome.
  45. HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements.
  46. ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota.
  1. Nat Commun. 2024 Feb 01. 15(1): 967
    Health in Africa.
      
    DOI:  https://doi.org/10.1038/s41467-024-45268-1
  2. Science. 2024 Feb 02. 383(6682): 562
    Baby in tow.
    Alexandra Hogan.
      
    DOI:  https://doi.org/10.1126/science.ado3078
  3. Nat Commun. 2024 Jan 27. 15(1): 807
    Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis.
    Ting Dong, Guangan Hu, Zhongqi Fan, Huirui Wang, Yinghui Gao, Sisi Wang, Hao Xu, Michael B Yaffe, Matthew G Vander Heiden, Guoyue Lv, Jianzhu Chen.
      Kupffer cells are liver resident macrophages and play critical role in fatty liver disease, yet the underlying mechanisms remain unclear. Here, we show that activation of G-protein coupled receptor 3 (GPR3) in Kupffer cells stimulates glycolysis and protects mice from obesity and fatty liver disease. GPR3 activation induces a rapid increase in glycolysis via formation of complexes between β-arrestin2 and key glycolytic enzymes as well as sustained increase in glycolysis through transcription of glycolytic genes. In mice, GPR3 activation in Kupffer cells results in enhanced glycolysis, reduced inflammation and inhibition of high-fat diet induced obesity and liver pathogenesis. In human fatty liver biopsies, GPR3 activation increases expression of glycolytic genes and reduces expression of inflammatory genes in a population of disease-associated macrophages. These findings identify GPR3 activation as a pivotal mechanism for metabolic reprogramming of Kupffer cells and as a potential approach for treating fatty liver disease.
    DOI:  https://doi.org/10.1038/s41467-024-45167-5
  4. Nature. 2024 Jan 31.
    Stress response silencing by an E3 ligase mutated in neurodegeneration.
    Diane L Haakonsen, Michael Heider, Andrew J Ingersoll, Kayla Vodehnal, Samuel R Witus, Takeshi Uenaka, Marius Wernig, Michael Rapé.
      Stress response pathways detect and alleviate adverse conditions to safeguard cell and tissue homeostasis, yet their prolonged activation induces apoptosis and disrupts organismal health1-3. How stress responses are turned off at the right time and place remains poorly understood. Here we report a ubiquitin-dependent mechanism that silences the cellular response to mitochondrial protein import stress. Crucial to this process is the silencing factor of the integrated stress response (SIFI), a large E3 ligase complex mutated in ataxia and in early-onset dementia that degrades both unimported mitochondrial precursors and stress response components. By recognizing bifunctional substrate motifs that equally encode protein localization and stability, the SIFI complex turns off a general stress response after a specific stress event has been resolved. Pharmacological stress response silencing sustains cell survival even if stress resolution failed, which underscores the importance of signal termination and provides a roadmap for treating neurodegenerative diseases caused by mitochondrial import defects.
    DOI:  https://doi.org/10.1038/s41586-023-06985-7
  5. Nat Commun. 2024 Feb 01. 15(1): 955
    Tissue-specific profiling of age-dependent miRNAomic changes in Caenorhabditis elegans.
    Xueqing Wang, Quanlong Jiang, Hongdao Zhang, Zhidong He, Yuanyuan Song, Yifan Chen, Na Tang, Yifei Zhou, Yiping Li, Adam Antebi, Ligang Wu, Jing-Dong J Han, Yidong Shen.
      Ageing exhibits common and distinct features in various tissues, making it critical to decipher the tissue-specific ageing mechanisms. MiRNAs are essential regulators in ageing and are recently highlighted as a class of intercellular messengers. However, little is known about the tissue-specific transcriptomic changes of miRNAs during ageing. C. elegans is a well-established model organism in ageing research. Here, we profile the age-dependent miRNAomic changes in five isolated worm tissues. Besides the diverse ageing-regulated miRNA expression across tissues, we discover numerous miRNAs in the tissues without their transcription. We further profile miRNAs in the extracellular vesicles and find that worm miRNAs undergo inter-tissue trafficking via these vesicles in an age-dependent manner. Using these datasets, we uncover the interaction between body wall muscle-derived mir-1 and DAF-16/FOXO in the intestine, suggesting mir-1 as a messenger in inter-tissue signalling. Taken together, we systematically investigate worm miRNAs in the somatic tissues and extracellular vesicles during ageing, providing a valuable resource to study tissue-autonomous and nonautonomous functions of miRNAs in ageing.
    DOI:  https://doi.org/10.1038/s41467-024-45249-4
  6. Nat Rev Immunol. 2024 Feb 01.
    Neutrophil surface RNAs promote entry to inflamed sites.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01000-0
  7. Science. 2024 Feb 02. 383(6682): 482-483
    Arterial pulses link heart-brain oscillations.
    Owen P Hamill.
      A central baroreceptor monitors arterial pressure to modulate brain activity.
    DOI:  https://doi.org/10.1126/science.adn4942
  8. Nat Commun. 2024 Jan 29. 15(1): 840
    CaMK4 controls follicular helper T cell expansion and function during normal and autoimmune T-dependent B cell responses.
    Marc Scherlinger, Hao Li, Wenliang Pan, Wei Li, Kohei Karino, Theodoros Vichos, Afroditi Boulougoura, Nobuya Yoshida, Maria G Tsokos, George C Tsokos.
      Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by dysregulated B cell compartment responsible for the production of autoantibodies. Here, we show that T cell-specific expression of calcium/calmodulin-dependent protein kinase IV (CaMK4) leads to T follicular helper (Tfh) cells expansion in models of T-dependent immunization and autoimmunity. Mechanistically, CaMK4 controls the Tfh-specific transcription factor B cell lymphoma 6 (Bcl6) at the transcriptional level through the cAMP responsive element modulator α (CREMα). In the absence of CaMK4 in T cells, germinal center formation and humoral immunity is impaired in immunized mice, resulting in reduced anti-dsDNA titres, as well as IgG and complement kidney deposition in the lupus-prone B6.lpr mouse. In human Tfh cells, CaMK4 inhibition reduced BCL6 expression and IL-21 secretion ex vivo, resulting in impaired plasmablast formation and IgG production. In patients with SLE, CAMK4 mRNA levels in Tfh cells correlated with those of BCL6. In conclusion, we identify CaMK4/CREMα as a driver of T cell-dependent B cell dysregulation in autoimmunity.
    DOI:  https://doi.org/10.1038/s41467-024-45080-x
  9. Nat Commun. 2024 Jan 31. 15(1): 940
    Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates.
    Yong Geun Jeon, Hahn Nahmgoong, Jiyoung Oh, Dabin Lee, Dong Wook Kim, Jane Eunsoo Kim, Ye Young Kim, Yul Ji, Ji Seul Han, Sung Min Kim, Jee Hyung Sohn, Won Taek Lee, Sun Won Kim, Jeu Park, Jin Young Huh, Kyuri Jo, Je-Yoel Cho, Jiyoung Park, Jae Bum Kim.
      In mammals, brown adipose tissue (BAT) and inguinal white adipose tissue (iWAT) execute sequential thermogenesis to maintain body temperature during cold stimuli. BAT rapidly generates heat through brown adipocyte activation, and further iWAT gradually stimulates beige fat cell differentiation upon prolonged cold challenges. However, fat depot-specific regulatory mechanisms for thermogenic activation of two fat depots are poorly understood. Here, we demonstrate that E3 ubiquitin ligase RNF20 orchestrates adipose thermogenesis with BAT- and iWAT-specific substrates. Upon cold stimuli, BAT RNF20 is rapidly downregulated, resulting in GABPα protein elevation by controlling protein stability, which stimulates thermogenic gene expression. Accordingly, BAT-specific Rnf20 suppression potentiates BAT thermogenic activity via GABPα upregulation. Moreover, upon prolonged cold stimuli, iWAT RNF20 is gradually upregulated to promote de novo beige adipogenesis. Mechanistically, iWAT RNF20 mediates NCoR1 protein degradation, rather than GABPα, to activate PPARγ. Together, current findings propose fat depot-specific regulatory mechanisms for temporal activation of adipose thermogenesis.
    DOI:  https://doi.org/10.1038/s41467-024-45270-7
  10. Immunity. 2024 Jan 24. pii: S1074-7613(24)00027-X. [Epub ahead of print]
    Microbiota-derived butyrate restricts tuft cell differentiation via histone deacetylase 3 to modulate intestinal type 2 immunity.
    Emily M Eshleman, Taylor Rice, Crystal Potter, Amanda Waddell, Seika Hashimoto-Hill, Vivienne Woo, Sydney Field, Laura Engleman, Hee-Woong Lim, Michael A Schumacher, Mark R Frey, Lee A Denson, Fred D Finkelman, Theresa Alenghat.
      Tuft cells in mucosal tissues are key regulators of type 2 immunity. Here, we examined the impact of the microbiota on tuft cell biology in the intestine. Succinate induction of tuft cells and type 2 innate lymphoid cells was elevated with loss of gut microbiota. Colonization with butyrate-producing bacteria or treatment with butyrate suppressed this effect and reduced intestinal histone deacetylase activity. Epithelial-intrinsic deletion of the epigenetic-modifying enzyme histone deacetylase 3 (HDAC3) inhibited tuft cell expansion in vivo and impaired type 2 immune responses during helminth infection. Butyrate restricted stem cell differentiation into tuft cells, and inhibition of HDAC3 in adult mice and human intestinal organoids blocked tuft cell expansion. Collectively, these data define a HDAC3 mechanism in stem cells for tuft cell differentiation that is dampened by a commensal metabolite, revealing a pathway whereby the microbiota calibrate intestinal type 2 immunity.
    Keywords:  HDAC3; butyrate; development; epigenetics; intestine; microbiota; organoid; stem cell; tuft cell; type 2 immunity
    DOI:  https://doi.org/10.1016/j.immuni.2024.01.002
  11. Nat Commun. 2024 Jan 30. 15(1): 890
    Rescuing SERCA2 pump deficiency improves bone mechano-responsiveness in type 2 diabetes by shaping osteocyte calcium dynamics.
    Xi Shao, Yulan Tian, Juan Liu, Zedong Yan, Yuanjun Ding, Xiaoxia Hao, Dan Wang, Liangliang Shen, Erping Luo, X Edward Guo, Peng Luo, Wenjing Luo, Jing Cai, Da Jing.
      Type 2 diabetes (T2D)-related fragility fractures represent an increasingly tough medical challenge, and the current treatment options are limited. Mechanical loading is essential for maintaining bone integrity, although bone mechano-responsiveness in T2D remains poorly characterized. Herein, we report that exogenous cyclic loading-induced improvements in bone architecture and strength are compromised in both genetically spontaneous and experimentally-induced T2D mice. T2D-induced reduction in bone mechano-responsiveness is directly associated with the weakened Ca2+ oscillatory dynamics of osteocytes, although not those of osteoblasts, which is dependent on PPARα-mediated specific reduction in osteocytic SERCA2 pump expression. Treatment with the SERCA2 agonist istaroxime was demonstrated to improve T2D bone mechano-responsiveness by rescuing osteocyte Ca2+ dynamics and the associated regulation of osteoblasts and osteoclasts. Moreover, T2D-induced deterioration of bone mechano-responsiveness is blunted in mice with osteocytic SERCA2 overexpression. Collectively, our study provides mechanistic insights into T2D-mediated deterioration of bone mechano-responsiveness and identifies a promising countermeasure against T2D-associated fragility fractures.
    DOI:  https://doi.org/10.1038/s41467-024-45023-6
  12. Sci Immunol. 2024 Feb 02. 9(92): eado2158
    Throwing IL-1β for a loop.
    Noah Jacobs, Gabriel K Griffin.
      The lncRNA AMANZI exerts cis-regulatory control of IL-1β-mediated inflammation.
    DOI:  https://doi.org/10.1126/sciimmunol.ado2158
  13. Nat Metab. 2024 Jan 29.
    Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation.
    Wenmin Xia, Preethi Veeragandham, Yu Cao, Yayun Xu, Torrey E Rhyne, Jiaxin Qian, Chao-Wei Hung, Peng Zhao, Ying Jones, Hui Gao, Christopher Liddle, Ruth T Yu, Michael Downes, Ronald M Evans, Mikael Rydén, Martin Wabitsch, Zichen Wang, Hiroyuki Hakozaki, Johannes Schöneberg, Shannon M Reilly, Jianfeng Huang, Alan R Saltiel.
      Mitochondrial dysfunction is a characteristic trait of human and rodent obesity, insulin resistance and fatty liver disease. Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA. RalA expression and activity are increased in white adipocytes after HFD. Targeted deletion of RalA in white adipocytes prevents fragmentation of mitochondria and diminishes HFD-induced weight gain by increasing fatty acid oxidation. Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation. Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance. Thus, chronic activation of RalA plays a key role in repressing energy expenditure in obese adipose tissue by shifting the balance of mitochondrial dynamics toward excessive fission, contributing to weight gain and metabolic dysfunction.
    DOI:  https://doi.org/10.1038/s42255-024-00978-0
  14. Nature. 2024 Jan 31.
    An epigenetic barrier sets the timing of human neuronal maturation.
    Gabriele Ciceri, Arianna Baggiolini, Hyein S Cho, Meghana Kshirsagar, Silvia Benito-Kwiecinski, Ryan M Walsh, Kelly A Aromolaran, Alberto J Gonzalez-Hernandez, Hermany Munguba, So Yeon Koo, Nan Xu, Kaylin J Sevilla, Peter A Goldstein, Joshua Levitz, Christina S Leslie, Richard P Koche, Lorenz Studer.
      The pace of human brain development is highly protracted compared with most other species1-7. The maturation of cortical neurons is particularly slow, taking months to years to develop adult functions3-5. Remarkably, such protracted timing is retained in cortical neurons derived from human pluripotent stem cells (hPSCs) during in vitro differentiation or upon transplantation into the mouse brain4,8,9. Those findings suggest the presence of a cell-intrinsic clock setting the pace of neuronal maturation, although the molecular nature of this clock remains unknown. Here we identify an epigenetic developmental programme that sets the timing of human neuronal maturation. First, we developed a hPSC-based approach to synchronize the birth of cortical neurons in vitro which enabled us to define an atlas of morphological, functional and molecular maturation. We observed a slow unfolding of maturation programmes, limited by the retention of specific epigenetic factors. Loss of function of several of those factors in cortical neurons enables precocious maturation. Transient inhibition of EZH2, EHMT1 and EHMT2 or DOT1L, at progenitor stage primes newly born neurons to rapidly acquire mature properties upon differentiation. Thus our findings reveal that the rate at which human neurons mature is set well before neurogenesis through the establishment of an epigenetic barrier in progenitor cells. Mechanistically, this barrier holds transcriptional maturation programmes in a poised state that is gradually released to ensure the prolonged timeline of human cortical neuron maturation.
    DOI:  https://doi.org/10.1038/s41586-023-06984-8
  15. J Exp Med. 2024 Mar 04. pii: e20231011. [Epub ahead of print]221(3):
    Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2.
    Chen Yu, Eleonora M Lad, Rose Mathew, Nobuhiko Shiraki, Sejiro Littleton, Yun Chen, Jinchao Hou, Kai Schlepckow, Simone Degan, Lindsey Chew, Joshua Amason, Joan Kalnitsky, Catherine Bowes Rickman, Alan D Proia, Marco Colonna, Christian Haass, Daniel R Saban.
      Outer retinal degenerations, including age-related macular degeneration (AMD), are characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. In these blinding diseases, macrophages accumulate at atrophic sites, but their ontogeny and niche specialization remain poorly understood, especially in humans. We uncovered a unique profile of microglia, marked by galectin-3 upregulation, at atrophic sites in mouse models of retinal degeneration and human AMD. In disease models, conditional deletion of galectin-3 in microglia led to phagocytosis defects and consequent augmented photoreceptor death, RPE damage, and vision loss, indicating protective roles. Mechanistically, Trem2 signaling orchestrated microglial migration to atrophic sites and induced galectin-3 expression. Moreover, pharmacologic Trem2 agonization led to heightened protection but in a galectin-3-dependent manner. In elderly human subjects, we identified this highly conserved microglial population that expressed galectin-3 and Trem2. This population was significantly enriched in the macular RPE-choroid of AMD subjects. Collectively, our findings reveal a neuroprotective population of microglia and a potential therapeutic target for mitigating retinal degeneration.
    DOI:  https://doi.org/10.1084/jem.20231011
  16. Immunity. 2024 Jan 29. pii: S1074-7613(23)00537-X. [Epub ahead of print]
    Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision.
    Kathleen Abadie, Elisa C Clark, Rajesh M Valanparambil, Obinna Ukogu, Wei Yang, Riza M Daza, Kenneth K H Ng, Jumana Fathima, Allan L Wang, Judong Lee, Tahseen H Nasti, Avinash Bhandoola, Armita Nourmohammad, Rafi Ahmed, Jay Shendure, Junyue Cao, Hao Yuan Kueh.
      The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cells it forms. This encoding emerges from lymphocyte decisions to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8+ T cells at the single-cell and clonal lineage level using time-resolved transcriptomics, quantitative live imaging, and an acute infection model, we find that T cells will maintain or lose memory potential early after antigen recognition. However, following pathogen clearance, T cells may regain memory potential if initially lost. Mechanistically, this flexibility is implemented by a stochastic cis-epigenetic switch that tunably and reversibly silences the memory regulator, TCF1, in response to stimulation. Mathematical modeling shows how this flexibility allows memory T cell numbers to scale robustly with pathogen virulence and immune response magnitudes. We propose that flexibility and stochasticity in cellular decisions ensure optimal immune responses against diverse threats.
    Keywords:  T cell differentiation; acute infection; cell fate decisions; immune memory; lineage plasticity; live-cell imaging; mathematical modeling; single-cell dynamics; systems immunology; time-resolved single-cell RNA-seq
    DOI:  https://doi.org/10.1016/j.immuni.2023.12.006
  17. Cell. 2024 Feb 01. pii: S0092-8674(24)00002-3. [Epub ahead of print]187(3): 733-749.e16
    Xist ribonucleoproteins promote female sex-biased autoimmunity.
    Diana R Dou, Yanding Zhao, Julia A Belk, Yang Zhao, Kerriann M Casey, Derek C Chen, Rui Li, Bingfei Yu, Suhas Srinivasan, Brian T Abe, Katerina Kraft, Ceke Hellström, Ronald Sjöberg, Sarah Chang, Allan Feng, Daniel W Goldman, Ami A Shah, Michelle Petri, Lorinda S Chung, David F Fiorentino, Emma K Lundberg, Anton Wutz, Paul J Utz, Howard Y Chang.
      Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
    Keywords:  RNA binding protein; XIST; autoantibody; autoimmunity; long non-coding RNA
    DOI:  https://doi.org/10.1016/j.cell.2023.12.037
  18. J Clin Invest. 2024 Feb 01. pii: e169064. [Epub ahead of print]134(3):
    KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss.
    Grant Kauwe, Kristeen A Pareja-Navarro, Lei Yao, Jackson H Chen, Ivy Wong, Rowan Saloner, Helen Cifuentes, Alissa L Nana, Samah Shah, Yaqiao Li, David Le, Salvatore Spina, Lea T Grinberg, William W Seeley, Joel H Kramer, Todd C Sacktor, Birgit Schilling, Li Gan, Kaitlin B Casaletto, Tara E Tracy.
      Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer's disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.
    Keywords:  Alzheimer disease; Memory; Neuroscience; Synapses
    DOI:  https://doi.org/10.1172/JCI169064
  19. EMBO Rep. 2024 Jan 30.
    A lncRNA Dleu2-encoded peptide relieves autoimmunity by facilitating Smad3-mediated Treg induction.
    Sibei Tang, Junxun Zhang, Fangzhou Lou, Hong Zhou, Xiaojie Cai, Zhikai Wang, Libo Sun, Yang Sun, Xiangxiao Li, Li Fan, Yan Li, Xinping Jin, Siyu Deng, Qianqian Yin, Jing Bai, Hong Wang, Honglin Wang.
      Micropeptides encoded by short open reading frames (sORFs) within long noncoding RNAs (lncRNAs) are beginning to be discovered and characterized as regulators of biological and pathological processes. Here, we find that lncRNA Dleu2 encodes a 17-amino-acid micropeptide, which we name Dleu2-17aa, that is abundantly expressed in T cells. Dleu2-17aa promotes inducible regulatory T (iTreg) cell generation by interacting with SMAD Family Member 3 (Smad3) and enhancing its binding to the Foxp3 conserved non-coding DNA sequence 1 (CNS1) region. Importantly, the genetic deletion of Dleu2-17aa in mice by start codon mutation impairs iTreg generation and worsens experimental autoimmune encephalomyelitis (EAE). Conversely, the exogenous supplementation of Dleu2-17aa relieves EAE. Our findings demonstrate an indispensable role of Dleu2-17aa in maintaining immune homeostasis and suggest therapeutic applications for this peptide in treating autoimmune diseases.
    Keywords:  Autoimmunity; Dleu2; LncRNA Encoded Micropeptide; Smad3; Treg Cell
    DOI:  https://doi.org/10.1038/s44319-024-00070-4
  20. Nature. 2024 Jan 31.
    Natural inhibitor found for cell death by ferroptosis.
    Donna D Zhang.
      
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-00080-1
  21. Sci Immunol. 2024 Feb 02. 9(92): eadi0042
    Precise CRISPR-Cas9 gene repair in autologous memory T cells to treat familial hemophagocytic lymphohistiocytosis.
    Xun Li, Tristan Wirtz, Timm Weber, Mikhail Lebedin, Elijah D Lowenstein, Thomas Sommermann, Andreas Zach, Tomoharu Yasuda, Kathrin de la Rosa, Van Trung Chu, Johannes H Schulte, Ingo Müller, Christine Kocks, Klaus Rajewsky.
      Familial hemophagocytic lymphohistiocytosis (FHL) is an inherited, often fatal immune deficiency characterized by severe systemic hyperinflammation. Although allogeneic bone marrow transplantation can be curative, more effective therapies are urgently needed. FHL is caused by inactivating mutations in proteins that regulate cellular immunity. Here, we used an adeno-associated virus-based CRISPR-Cas9 system with an inhibitor of nonhomologous end joining to repair such mutations in potentially long-lived T cells ex vivo. Repaired CD8 memory T cells efficiently cured lethal hyperinflammation in a mouse model of Epstein-Barr virus-triggered FHL2, a subtype caused by perforin-1 (Prf1) deficiency. Furthermore, repair of PRF1 and Munc13-4 (UNC13D)-whose deficiency causes the FHL subtype FHL3-in mutant memory T cells from two critically ill patients with FHL restored T cell cytotoxicity. These results provide a starting point for the treatment of genetic T cell immune dysregulation syndromes with repaired autologous T cells.
    DOI:  https://doi.org/10.1126/sciimmunol.adi0042
  22. Sci Immunol. 2024 Feb 02. 9(92): eado2161
    Promoting (and targeting) alternative expression.
    Asha Pillai.
      Lineage-specific effects of upstream promoters affect ST2 expression and effector function in TH1cells.
    DOI:  https://doi.org/10.1126/sciimmunol.ado2161
  23. Nat Commun. 2024 Jan 31. 15(1): 319
    GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.
    Yuki Ishikawa, Nao Tanaka, Yoshihide Asano, Masanari Kodera, Yuichiro Shirai, Mitsuteru Akahoshi, Minoru Hasegawa, Takashi Matsushita, Kazuyoshi Saito, Sei-Ichiro Motegi, Hajime Yoshifuji, Ayumi Yoshizaki, Tomohiro Kohmoto, Kae Takagi, Akira Oka, Miho Kanda, Yoshihito Tanaka, Yumi Ito, Kazuhisa Nakano, Hiroshi Kasamatsu, Akira Utsunomiya, Akiko Sekiguchi, Hiroaki Niiro, Masatoshi Jinnin, Katsunari Makino, Takamitsu Makino, Hironobu Ihn, Motohisa Yamamoto, Chisako Suzuki, Hiroki Takahashi, Emi Nishida, Akimichi Morita, Toshiyuki Yamamoto, Manabu Fujimoto, Yuya Kondo, Daisuke Goto, Takayuki Sumida, Naho Ayuzawa, Hidetoshi Yanagida, Tetsuya Horita, Tatsuya Atsumi, Hirahito Endo, Yoshihito Shima, Atsushi Kumanogoh, Jun Hirata, Nao Otomo, Hiroyuki Suetsugu, Yoshinao Koike, Kohei Tomizuka, Soichiro Yoshino, Xiaoxi Liu, Shuji Ito, Keiko Hikino, Akari Suzuki, Yukihide Momozawa, Shiro Ikegawa, Yoshiya Tanaka, Osamu Ishikawa, Kazuhiko Takehara, Takeshi Torii, Shinichi Sato, Yukinori Okada, Tsuneyo Mimori, Fumihiko Matsuda, Koichi Matsuda, Tiffany Amariuta, Issei Imoto, Keitaro Matsuo, Masataka Kuwana, Yasushi Kawaguchi, Koichiro Ohmura, Chikashi Terao.
      Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.
    DOI:  https://doi.org/10.1038/s41467-023-44541-z
  24. Nature. 2024 Jan 31.
    Why human brain cells grow so slowly.
    Shamini Bundell.
      
    Keywords:  Ageing; Cell biology; Epigenetics; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-00280-9
  25. Nat Commun. 2024 Feb 01. 15(1): 966
    Neutral ceramidase regulates breast cancer progression by metabolic programming of TREM2-associated macrophages.
    Rui Sun, Chao Lei, Zhishan Xu, Xuemei Gu, Liu Huang, Liang Chen, Yi Tan, Min Peng, Kavitha Yaddanapudi, Leah Siskind, Maiying Kong, Robert Mitchell, Jun Yan, Zhongbin Deng.
      The tumor microenvironment is reprogrammed by cancer cells and participates in all stages of tumor progression. Neutral ceramidase is a key regulator of ceramide, the central intermediate in sphingolipid metabolism. The contribution of neutral ceramidase to the reprogramming of the tumor microenvironment is not well understood. Here, we find that deletion of neutral ceramidase in multiple breast cancer models in female mice accelerates tumor growth. Our result show that Ly6C+CD39+ tumor-infiltrating CD8 T cells are enriched in the tumor microenvironment and display an exhausted phenotype. Deletion of myeloid neutral ceramidase in vivo and in vitro induces exhaustion in tumor-infiltrating Ly6C+CD39+CD8+ T cells. Mechanistically, myeloid neutral ceramidase is required for the generation of lipid droplets and for the induction of lipolysis, which generate fatty acids for fatty-acid oxidation and orchestrate macrophage metabolism. Metabolite ceramide leads to reprogramming of macrophages toward immune suppressive TREM2+ tumor associated macrophages, which promote CD8 T cells exhaustion.
    DOI:  https://doi.org/10.1038/s41467-024-45084-7
  26. Nat Immunol. 2024 Feb 02.
    Mapping brain-immune interactions in ischemic stroke.
    Danye Jiang, Louise McCullough.
      
    DOI:  https://doi.org/10.1038/s41590-024-01747-7
  27. Nature. 2024 Jan 31.
    Matrix viscoelasticity promotes liver cancer progression in the pre-cirrhotic liver.
    Weiguo Fan, Kolade Adebowale, Lóránd Váncza, Yuan Li, Md Foysal Rabbi, Koshi Kunimoto, Dongning Chen, Gergely Mozes, David Kung-Chun Chiu, Yisi Li, Junyan Tao, Yi Wei, Nia Adeniji, Ryan L Brunsing, Renumathy Dhanasekaran, Aatur Singhi, David Geller, Su Hao Lo, Louis Hodgson, Edgar G Engleman, Gregory W Charville, Vivek Charu, Satdarshan P Monga, Taeyoon Kim, Rebecca G Wells, Ovijit Chaudhuri, Natalie J Török.
      Type 2 diabetes mellitus is a major risk factor for hepatocellular carcinoma (HCC). Changes in extracellular matrix (ECM) mechanics contribute to cancer development1,2, and increased stiffness is known to promote HCC progression in cirrhotic conditions3,4. Type 2 diabetes mellitus is characterized by an accumulation of advanced glycation end-products (AGEs) in the ECM; however, how this affects HCC in non-cirrhotic conditions is unclear. Here we find that, in patients and animal models, AGEs promote changes in collagen architecture and enhance ECM viscoelasticity, with greater viscous dissipation and faster stress relaxation, but not changes in stiffness. High AGEs and viscoelasticity combined with oncogenic β-catenin signalling promote HCC induction, whereas inhibiting AGE production, reconstituting the AGE clearance receptor AGER1 or breaking AGE-mediated collagen cross-links reduces viscoelasticity and HCC growth. Matrix analysis and computational modelling demonstrate that lower interconnectivity of AGE-bundled collagen matrix, marked by shorter fibre length and greater heterogeneity, enhances viscoelasticity. Mechanistically, animal studies and 3D cell cultures show that enhanced viscoelasticity promotes HCC cell proliferation and invasion through an integrin-β1-tensin-1-YAP mechanotransductive pathway. These results reveal that AGE-mediated structural changes enhance ECM viscoelasticity, and that viscoelasticity can promote cancer progression in vivo, independent of stiffness.
    DOI:  https://doi.org/10.1038/s41586-023-06991-9
  28. Nat Rev Immunol. 2024 Feb 02.
    The immunology of type 1 diabetes.
    Kevan C Herold, Thomas Delong, Ana Luisa Perdigoto, Noah Biru, Todd M Brusko, Lucy S K Walker.
      Following the seminal discovery of insulin a century ago, treatment of individuals with type 1 diabetes (T1D) has been largely restricted to efforts to monitor and treat metabolic glucose dysregulation. The recent regulatory approval of the first immunotherapy that targets T cells as a means to delay the autoimmune destruction of pancreatic β-cells highlights the critical role of the immune system in disease pathogenesis and tends to pave the way for other immune-targeted interventions for T1D. Improving the efficacy of such interventions across the natural history of the disease will probably require a more detailed understanding of the immunobiology of T1D, as well as technologies to monitor residual β-cell mass and function. Here we provide an overview of the immune mechanisms that underpin the pathogenesis of T1D, with a particular emphasis on T cells.
    DOI:  https://doi.org/10.1038/s41577-023-00985-4
  29. Nat Commun. 2024 Jan 31. 15(1): 945
    Effect of aging on the human myometrium at single-cell resolution.
    Paula Punzon-Jimenez, Alba Machado-Lopez, Raul Perez-Moraga, Jaime Llera-Oyola, Daniela Grases, Marta Galvez-Viedma, Mustafa Sibai, Elena Satorres-Perez, Susana Lopez-Agullo, Rafael Badenes, Carolina Ferrer-Gomez, Eduard Porta-Pardo, Beatriz Roson, Carlos Simon, Aymara Mas.
      Age-associated myometrial dysfunction can prompt complications during pregnancy and labor, which is one of the factors contributing to the 7.8-fold increase in maternal mortality in women over 40. Using single-cell/single-nucleus RNA sequencing and spatial transcriptomics, we have constructed a cellular atlas of the aging myometrium from 186,120 cells across twenty perimenopausal and postmenopausal women. We identify 23 myometrial cell subpopulations, including contractile and venous capillary cells as well as immune-modulated fibroblasts. Myometrial aging leads to fewer contractile capillary cells, a reduced level of ion channel expression in smooth muscle cells, and impaired gene expression in endothelial, smooth muscle, fibroblast, perivascular, and immune cells. We observe altered myometrial cell-to-cell communication as an aging hallmark, which associated with the loss of 25 signaling pathways, including those related to angiogenesis, tissue repair, contractility, immunity, and nervous system regulation. These insights may contribute to a better understanding of the complications faced by older individuals during pregnancy and labor.
    DOI:  https://doi.org/10.1038/s41467-024-45143-z
  30. Nat Commun. 2024 Feb 01. 15(1): 953
    Mitochondrial protein C15ORF48 is a stress-independent inducer of autophagy that regulates oxidative stress and autoimmunity.
    Yuki Takakura, Moeka Machida, Natsumi Terada, Yuka Katsumi, Seika Kawamura, Kenta Horie, Maki Miyauchi, Tatsuya Ishikawa, Nobuko Akiyama, Takao Seki, Takahisa Miyao, Mio Hayama, Rin Endo, Hiroto Ishii, Yuya Maruyama, Naho Hagiwara, Tetsuya J Kobayashi, Naoto Yamaguchi, Hiroyuki Takano, Taishin Akiyama, Noritaka Yamaguchi.
      Autophagy is primarily activated by cellular stress, such as starvation or mitochondrial damage. However, stress-independent autophagy is activated by unclear mechanisms in several cell types, such as thymic epithelial cells (TECs). Here we report that the mitochondrial protein, C15ORF48, is a critical inducer of stress-independent autophagy. Mechanistically, C15ORF48 reduces the mitochondrial membrane potential and lowers intracellular ATP levels, thereby activating AMP-activated protein kinase and its downstream Unc-51-like kinase 1. Interestingly, C15ORF48-dependent induction of autophagy upregulates intracellular glutathione levels, promoting cell survival by reducing oxidative stress. Mice deficient in C15orf48 show a reduction in stress-independent autophagy in TECs, but not in typical starvation-induced autophagy in skeletal muscles. Moreover, C15orf48-/- mice develop autoimmunity, which is consistent with the fact that the stress-independent autophagy in TECs is crucial for the thymic self-tolerance. These results suggest that C15ORF48 induces stress-independent autophagy, thereby regulating oxidative stress and self-tolerance.
    DOI:  https://doi.org/10.1038/s41467-024-45206-1
  31. Nat Rev Immunol. 2024 Jan 30.
    Age-related motor deficits caused by clonal haematopoiesis-driven, monocyte-derived microglia.
    Austeja Baleviciute, Lily Keane.
      
    DOI:  https://doi.org/10.1038/s41577-024-00997-8
  32. Sci Signal. 2024 Jan 30. 17(821): eadg2622
    Pannexin-3 stabilizes the transcription factor Bcl6 in a channel-independent manner to protect against vascular oxidative stress.
    Abigail G Wolpe, Melissa A Luse, Christopher Baryiames, Wyatt J Schug, Jacob B Wolpe, Scott R Johnstone, Luke S Dunaway, Zuzanna J Juśkiewicz, Skylar A Loeb, Henry R Askew Page, Yen-Lin Chen, Vikram Sabapathy, Caitlin M Pavelec, Brent Wakefield, Eugenia Cifuentes-Pagano, Mykhaylo V Artamonov, Avril V Somlyo, Adam C Straub, Rahul Sharma, Frank Beier, Eugene J Barrett, Norbert Leitinger, Patrick J Pagano, Swapnil K Sonkusare, Stefanie Redemann, Linda Columbus, Silvia Penuela, Brant E Isakson.
      Targeted degradation regulates the activity of the transcriptional repressor Bcl6 and its ability to suppress oxidative stress and inflammation. Here, we report that abundance of endothelial Bcl6 is determined by its interaction with Golgi-localized pannexin 3 (Panx3) and that Bcl6 transcriptional activity protects against vascular oxidative stress. Consistent with data from obese, hypertensive humans, mice with an endothelial cell-specific deficiency in Panx3 had spontaneous systemic hypertension without obvious changes in channel function, as assessed by Ca2+ handling, ATP amounts, or Golgi luminal pH. Panx3 bound to Bcl6, and its absence reduced Bcl6 protein abundance, suggesting that the interaction with Panx3 stabilized Bcl6 by preventing its degradation. Panx3 deficiency was associated with increased expression of the gene encoding the H2O2-producing enzyme Nox4, which is normally repressed by Bcl6, resulting in H2O2-induced oxidative damage in the vasculature. Catalase rescued impaired vasodilation in mice lacking endothelial Panx3. Administration of a newly developed peptide to inhibit the Panx3-Bcl6 interaction recapitulated the increase in Nox4 expression and in blood pressure seen in mice with endothelial Panx3 deficiency. Panx3-Bcl6-Nox4 dysregulation occurred in obesity-related hypertension, but not when hypertension was induced in the absence of obesity. Our findings provide insight into a channel-independent role of Panx3 wherein its interaction with Bcl6 determines vascular oxidative state, particularly under the adverse conditions of obesity.
    DOI:  https://doi.org/10.1126/scisignal.adg2622
  33. Nat Commun. 2024 Feb 02. 15(1): 988
    Rescue of mitochondrial import failure by intercellular organellar transfer.
    Hope I Needs, Emily Glover, Gonçalo C Pereira, Alina Witt, Wolfgang Hübner, Mark P Dodding, Jeremy M Henley, Ian Collinson.
      Mitochondria are the powerhouses of eukaryotic cells, composed mostly of nuclear-encoded proteins imported from the cytosol. Thus, problems with the import machinery will disrupt their regenerative capacity and the cell's energy supplies - particularly troublesome for energy-demanding cells of nervous tissue and muscle. Unsurprisingly then, import breakdown is implicated in disease. Here, we explore the consequences of import failure in mammalian cells; wherein, blocking the import machinery impacts mitochondrial ultra-structure and dynamics, but, surprisingly, does not affect import. Our data are consistent with a response involving intercellular mitochondrial transport via tunnelling nanotubes to import healthy mitochondria and jettison those with blocked import sites. These observations support the existence of a widespread mechanism for the rescue of mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-024-45283-2
  34. Nat Commun. 2024 Jan 30. 15(1): 905
    Humoral profiles of toddlers and young children following SARS-CoV-2 mRNA vaccination.
    Nadège Nziza, Yixiang Deng, Lianna Wood, Navneet Dhanoa, Naomi Dulit-Greenberg, Tina Chen, Abigail S Kane, Zoe Swank, Jameson P Davis, Melina Demokritou, Anagha P Chitnis, Alessio Fasano, Andrea G Edlow, Nitya Jain, Bruce H Horwitz, Ryan P McNamara, David R Walt, Douglas A Lauffenburger, Boris Julg, Wayne G Shreffler, Galit Alter, Lael M Yonker.
      Although young children generally experience mild symptoms following infection with SARS-CoV-2, severe acute and long-term complications can occur. SARS-CoV-2 mRNA vaccines elicit robust immunoglobulin profiles in children ages 5 years and older, and in adults, corresponding with substantial protection against hospitalizations and severe disease. Whether similar immune responses and humoral protection can be observed in vaccinated infants and young children, who have a developing and vulnerable immune system, remains poorly understood. To study the impact of mRNA vaccination on the humoral immunity of infant, we use a system serology approach to comprehensively profile antibody responses in a cohort of children ages 6 months to 5 years who were vaccinated with the mRNA-1273 COVID-19 vaccine (25 μg). Responses are compared with vaccinated adults (100 μg), in addition to naturally infected toddlers and young children. Despite their lower vaccine dose, vaccinated toddlers elicit a functional antibody response as strong as adults, with higher antibody-dependent phagocytosis compared to adults, without report of side effects. Moreover, mRNA vaccination is associated with a higher IgG3-dependent humoral profile against SARS-CoV-2 compared to natural infection, supporting that mRNA vaccination is effective at eliciting a robust antibody response in toddlers and young children.
    DOI:  https://doi.org/10.1038/s41467-024-45181-7
  35. Nature. 2024 Jan 31.
    Single-neuronal elements of speech production in humans.
    Arjun R Khanna, William Muñoz, Young Joon Kim, Yoav Kfir, Angelique C Paulk, Mohsen Jamali, Jing Cai, Martina L Mustroph, Irene Caprara, Richard Hardstone, Mackenna Mejdell, Domokos Meszéna, Abigail Zuckerman, Jeffrey Schweitzer, Sydney Cash, Ziv M Williams.
      Humans are capable of generating extraordinarily diverse articulatory movement combinations to produce meaningful speech. This ability to orchestrate specific phonetic sequences, and their syllabification and inflection over subsecond timescales allows us to produce thousands of word sounds and is a core component of language1,2. The fundamental cellular units and constructs by which we plan and produce words during speech, however, remain largely unknown. Here, using acute ultrahigh-density Neuropixels recordings capable of sampling across the cortical column in humans, we discover neurons in the language-dominant prefrontal cortex that encoded detailed information about the phonetic arrangement and composition of planned words during the production of natural speech. These neurons represented the specific order and structure of articulatory events before utterance and reflected the segmentation of phonetic sequences into distinct syllables. They also accurately predicted the phonetic, syllabic and morphological components of upcoming words and showed a temporally ordered dynamic. Collectively, we show how these mixtures of cells are broadly organized along the cortical column and how their activity patterns transition from articulation planning to production. We also demonstrate how these cells reliably track the detailed composition of consonant and vowel sounds during perception and how they distinguish processes specifically related to speaking from those related to listening. Together, these findings reveal a remarkably structured organization and encoding cascade of phonetic representations by prefrontal neurons in humans and demonstrate a cellular process that can support the production of speech.
    DOI:  https://doi.org/10.1038/s41586-023-06982-w
  36. Sci Transl Med. 2024 Jan 31. 16(732): eadg6229
    TGF-βR2 signaling coordinates pulmonary vascular repair after viral injury in mice and human tissue.
    Gan Zhao, Lulu Xue, Aaron I Weiner, Ningqiang Gong, Stephanie Adams-Tzivelekidis, Joanna Wong, Maria E Gentile, Ana N Nottingham, Maria C Basil, Susan M Lin, Terren K Niethamer, Joshua M Diamond, Christian A Bermudez, Edward Cantu, Xuexiang Han, Yaqi Cao, Mohamad-Gabriel Alameh, Drew Weissman, Edward E Morrisey, Michael J Mitchell, Andrew E Vaughan.
      Disruption of pulmonary vascular homeostasis is a central feature of viral pneumonia, wherein endothelial cell (EC) death and subsequent angiogenic responses are critical determinants of the outcome of severe lung injury. A more granular understanding of the fundamental mechanisms driving reconstitution of lung endothelium is necessary to facilitate therapeutic vascular repair. Here, we demonstrated that TGF-β signaling through TGF-βR2 (transforming growth factor-β receptor 2) is activated in pulmonary ECs upon influenza infection, and mice deficient in endothelial Tgfbr2 exhibited prolonged injury and diminished vascular repair. Loss of endothelial Tgfbr2 prevented autocrine Vegfa (vascular endothelial growth factor α) expression, reduced endothelial proliferation, and impaired renewal of aerocytes thought to be critical for alveolar gas exchange. Angiogenic responses through TGF-βR2 were attributable to leucine-rich α-2-glycoprotein 1, a proangiogenic factor that counterbalances canonical angiostatic TGF-β signaling. Further, we developed a lipid nanoparticle that targets the pulmonary endothelium, Lung-LNP (LuLNP). Delivery of Vegfa mRNA, a critical TGF-βR2 downstream effector, by LuLNPs improved the impaired regeneration phenotype of EC Tgfbr2 deficiency during influenza injury. These studies defined a role for TGF-βR2 in lung endothelial repair and demonstrated efficacy of an efficient and safe endothelial-targeted LNP capable of delivering therapeutic mRNA cargo for vascular repair in influenza infection.
    DOI:  https://doi.org/10.1126/scitranslmed.adg6229
  37. Nat Biotechnol. 2024 Feb 01.
    Ultra-fast label-free quantification and comprehensive proteome coverage with narrow-window data-independent acquisition.
    Ulises H Guzman, Ana Martinez-Val, Zilu Ye, Eugen Damoc, Tabiwang N Arrey, Anna Pashkova, Santosh Renuse, Eduard Denisov, Johannes Petzoldt, Amelia C Peterson, Florian Harking, Ole Østergaard, Rasmus Rydbirk, Susana Aznar, Hamish Stewart, Yue Xuan, Daniel Hermanson, Stevan Horning, Christian Hock, Alexander Makarov, Vlad Zabrouskov, Jesper V Olsen.
      Mass spectrometry (MS)-based proteomics aims to characterize comprehensive proteomes in a fast and reproducible manner. Here we present the narrow-window data-independent acquisition (nDIA) strategy consisting of high-resolution MS1 scans with parallel tandem MS (MS/MS) scans of ~200 Hz using 2-Th isolation windows, dissolving the differences between data-dependent and -independent methods. This is achieved by pairing a quadrupole Orbitrap mass spectrometer with the asymmetric track lossless (Astral) analyzer which provides >200-Hz MS/MS scanning speed, high resolving power and sensitivity, and low-ppm mass accuracy. The nDIA strategy enables profiling of >100 full yeast proteomes per day, or 48 human proteomes per day at the depth of ~10,000 human protein groups in half-an-hour or ~7,000 proteins in 5 min, representing 3× higher coverage compared with current state-of-the-art MS. Multi-shot acquisition of offline fractionated samples provides comprehensive coverage of human proteomes in ~3 h. High quantitative precision and accuracy are demonstrated in a three-species proteome mixture, quantifying 14,000+ protein groups in a single half-an-hour run.
    DOI:  https://doi.org/10.1038/s41587-023-02099-7
  38. Nat Cell Biol. 2024 Feb 01.
    Mechanical forces across compartments coordinate cell shape and fate transitions to generate tissue architecture.
    Clémentine Villeneuve, Ali Hashmi, Irene Ylivinkka, Elizabeth Lawson-Keister, Yekaterina A Miroshnikova, Carlos Pérez-González, Satu-Marja Myllymäki, Fabien Bertillot, Bhagwan Yadav, Tao Zhang, Danijela Matic Vignjevic, Marja L Mikkola, M Lisa Manning, Sara A Wickström.
      Morphogenesis and cell state transitions must be coordinated in time and space to produce a functional tissue. An excellent paradigm to understand the coupling of these processes is mammalian hair follicle development, which is initiated by the formation of an epithelial invagination-termed placode-that coincides with the emergence of a designated hair follicle stem cell population. The mechanisms directing the deformation of the epithelium, cell state transitions and physical compartmentalization of the placode are unknown. Here we identify a key role for coordinated mechanical forces stemming from contractile, proliferative and proteolytic activities across the epithelial and mesenchymal compartments in generating the placode structure. A ring of fibroblast cells gradually wraps around the placode cells to generate centripetal contractile forces, which, in collaboration with polarized epithelial myosin activity, promote elongation and local tissue thickening. These mechanical stresses further enhance compartmentalization of Sox9 expression to promote stem cell positioning. Subsequently, proteolytic remodelling locally softens the basement membrane to facilitate a release of pressure on the placode, enabling localized cell divisions, tissue fluidification and epithelial invagination into the underlying mesenchyme. Together, our experiments and modelling identify dynamic cell shape transformations and tissue-scale mechanical cooperation as key factors for orchestrating organ formation.
    DOI:  https://doi.org/10.1038/s41556-023-01332-4
  39. Cell. 2024 Jan 23. pii: S0092-8674(24)00004-7. [Epub ahead of print]
    A 25-year odyssey of genomic technology advances and structural variant discovery.
    David Porubsky, Evan E Eichler.
      This perspective focuses on advances in genome technology over the last 25 years and their impact on germline variant discovery within the field of human genetics. The field has witnessed tremendous technological advances from microarrays to short-read sequencing and now long-read sequencing. Each technology has provided genome-wide access to different classes of human genetic variation. We are now on the verge of comprehensive variant detection of all forms of variation for the first time with a single assay. We predict that this transition will further transform our understanding of human health and biology and, more importantly, provide novel insights into the dynamic mutational processes shaping our genomes.
    Keywords:  chromosomal microarrays; human genomic disorders; long-read sequencing; next-generation sequencing; phased genome assembly; structural variation
    DOI:  https://doi.org/10.1016/j.cell.2024.01.002
  40. Nature. 2024 Feb;626(7997): 40-42
    Snapshots of genetic copy-and-paste machinery in action.
    Gael Cristofari.
      
    Keywords:  Biochemistry; Molecular biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-024-00112-w
  41. Sci Adv. 2024 Feb 02. 10(5): eadi9091
    H3K27M neoepitope vaccination in diffuse midline glioma induces B and T cell responses across diverse HLA loci of a recovered patient.
    Tamara Boschert, Kristina Kromer, Taga Lerner, Katharina Lindner, Gordon Haltenhof, Chin Leng Tan, Kristine Jähne, Isabel Poschke, Lukas Bunse, Philipp Eisele, Niklas Grassl, Iris Mildenberger, Katharina Sahm, Michael Platten, John M Lindner, Edward W Green.
      H3K27M, a driver mutation with T and B cell neoepitope characteristics, defines an aggressive subtype of diffuse glioma with poor survival. We functionally dissect the immune response of one patient treated with an H3K27M peptide vaccine who subsequently entered complete remission. The vaccine robustly expanded class II human leukocyte antigen (HLA)-restricted peripheral H3K27M-specific T cells. Using functional assays, we characterized 34 clonally unique H3K27M-reactive T cell receptors and identified critical, conserved motifs in their complementarity-determining region 3 regions. Using detailed HLA mapping, we further demonstrate that diverse HLA-DQ and HLA-DR alleles present immunogenic H3K27M epitopes. Furthermore, we identified and profiled H3K27M-reactive B cell receptors from activated B cells in the cerebrospinal fluid. Our results uncover the breadth of the adaptive immune response against a shared clonal neoantigen across multiple HLA allelotypes and support the use of class II-restricted peptide vaccines to stimulate tumor-specific T and B cells harboring receptors with therapeutic potential.
    DOI:  https://doi.org/10.1126/sciadv.adi9091
  42. Nat Commun. 2024 Jan 29. 15(1): 872
    Semi-supervised integration of single-cell transcriptomics data.
    Massimo Andreatta, Léonard Hérault, Paul Gueguen, David Gfeller, Ariel J Berenstein, Santiago J Carmona.
      Batch effects in single-cell RNA-seq data pose a significant challenge for comparative analyses across samples, individuals, and conditions. Although batch effect correction methods are routinely applied, data integration often leads to overcorrection and can result in the loss of biological variability. In this work we present STACAS, a batch correction method for scRNA-seq that leverages prior knowledge on cell types to preserve biological variability upon integration. Through an open-source benchmark, we show that semi-supervised STACAS outperforms state-of-the-art unsupervised methods, as well as supervised methods such as scANVI and scGen. STACAS scales well to large datasets and is robust to incomplete and imprecise input cell type labels, which are commonly encountered in real-life integration tasks. We argue that the incorporation of prior cell type information should be a common practice in single-cell data integration, and we provide a flexible framework for semi-supervised batch effect correction.
    DOI:  https://doi.org/10.1038/s41467-024-45240-z
  43. Sci Adv. 2024 Feb 02. 10(5): eadk1034
    Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.
    Wei Zhang, Minjie Zhang, Li Ma, Supawadee Jariyasakulroj, Qing Chang, Ziying Lin, Zhipeng Lu, Jian-Fu Chen.
      Animal or human models recapitulating brain ribosomopathies are incomplete, hampering development of urgently needed therapies. Here, we generated genetic mouse and human cerebral organoid models of brain ribosomopathies, caused by mutations in small nucleolar RNA (snoRNA) SNORD118. Both models exhibited protein synthesis loss, proteotoxic stress, and p53 activation and led to decreased proliferation and increased death of neural progenitor cells (NPCs), resulting in brain growth retardation, recapitulating features in human patients. Loss of SNORD118 function resulted in an aberrant upregulation of p-eIF2α, the mediator of integrated stress response (ISR). Using human iPSC cell-based screen, we identified small-molecule 2BAct, an ISR inhibitor, which potently reverses mutant NPC defects. Targeting ISR by 2BAct mitigated ribosomopathy defects in both cerebral organoid and mouse models. Thus, our SNORD118 mutant organoid and mice recapitulate human brain ribosomopathies and cross-validate maladaptive ISR as a key disease-driving mechanism, pointing to a therapeutic intervention strategy.
    DOI:  https://doi.org/10.1126/sciadv.adk1034
  44. J Exp Med. 2024 Feb 05. pii: e20232265. [Epub ahead of print]221(2):
    Unraveling the Tcrb interactome.
    Noah Ollikainen, Ranjan Sen.
      In this issue of JEM, Allyn et al. (https://doi.org/10.1084/jem.20230985) provide mechanistic insights into the nuclear organization of the Tcrb locus that permits long-range genomic rearrangements.
    DOI:  https://doi.org/10.1084/jem.20232265
  45. Commun Biol. 2024 01 31. 7(1): 144
    HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements.
    Avinash Thakur, Kwangjin Park, Rebecca Cullum, Bettina M Fuglerud, Mina Khoshnoodi, Sibyl Drissler, Tabea L Stephan, Jeremy Lotto, Donghwan Kim, Frank J Gonzalez, Pamela A Hoodless.
      Hepatocyte nuclear factor 4A (HNF4A/NR2a1), a transcriptional regulator of hepatocyte identity, controls genes that are crucial for liver functions, primarily through binding to enhancers. In mammalian cells, active and primed enhancers are marked by monomethylation of histone 3 (H3) at lysine 4 (K4) (H3K4me1) in a cell type-specific manner. How this modification is established and maintained at enhancers in connection with transcription factors (TFs) remains unknown. Using analysis of genome-wide histone modifications, TF binding, chromatin accessibility and gene expression, we show that HNF4A is essential for an active chromatin state. Using HNF4A loss and gain of function experiments in vivo and in cell lines in vitro, we show that HNF4A affects H3K4me1, H3K27ac and chromatin accessibility, highlighting its contribution to the establishment and maintenance of a transcriptionally permissive epigenetic state. Mechanistically, HNF4A interacts with the mixed-lineage leukaemia 4 (MLL4) complex facilitating recruitment to HNF4A-bound regions. Our findings indicate that HNF4A enriches H3K4me1, H3K27ac and establishes chromatin opening at transcriptional regulatory regions.
    DOI:  https://doi.org/10.1038/s42003-024-05835-0
  46. Cell Death Dis. 2024 Feb 01. 15(2): 105
    ACOD1 deficiency offers protection in a mouse model of diet-induced obesity by maintaining a healthy gut microbiota.
    Tanja Eberhart, Federico Uchenna Stanley, Luisa Ricci, Tiziana Chirico, Roberto Ferrarese, Sofia Sisti, Alessandra Scagliola, Andreina Baj, Sylvia Badurek, Andreas Sommer, Rachel Culp-Hill, Monika Dzieciatkowska, Engy Shokry, David Sumpton, Angelo D'Alessandro, Nicola Clementi, Nicasio Mancini, Simone Cardaci.
      Aconitate decarboxylase 1 (ACOD1) is the enzyme synthesizing itaconate, an immuno-regulatory metabolite tuning host-pathogen interactions. Such functions are achieved by affecting metabolic pathways regulating inflammation and microbe survival. However, at the whole-body level, metabolic roles of itaconate remain largely unresolved. By using multiomics-integrated approaches, here we show that ACOD1 responds to high-fat diet consumption in mice by promoting gut microbiota alterations supporting metabolic disease. Genetic disruption of itaconate biosynthesis protects mice against obesity, alterations in glucose homeostasis and liver metabolic dysfunctions by decreasing meta-inflammatory responses to dietary lipid overload. Mechanistically, fecal metagenomics and microbiota transplantation experiments demonstrate such effects are dependent on an amelioration of the intestinal ecosystem composition, skewed by high-fat diet feeding towards obesogenic phenotype. In particular, unbiased fecal microbiota profiling and axenic culture experiments point towards a primary role for itaconate in inhibiting growth of Bacteroidaceae and Bacteroides, family and genus of Bacteroidetes phylum, the major gut microbial taxon associated with metabolic health. Specularly to the effects imposed by Acod1 deficiency on fecal microbiota, oral itaconate consumption enhances diet-induced gut dysbiosis and associated obesogenic responses in mice. Unveiling an unrecognized role of itaconate, either endogenously produced or exogenously administered, in supporting microbiota alterations underlying diet-induced obesity in mice, our study points ACOD1 as a target against inflammatory consequences of overnutrition.
    DOI:  https://doi.org/10.1038/s41419-024-06483-2
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