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BACH2 regulates diversification of regulatory and proinflammatory chromatin states in TH17 cells.
Thakore, Pratiksha I; Schnell, Alexandra; Huang, Linglin; Zhao, Maryann; Hou, Yu; Christian, Elena; Zaghouani, Sarah; Wang, Chao; Singh, Vasundhara; Singaraju, Anvita; Krishnan, Rajesh Kumar; Kozoriz, Deneen; Ma, Sai; Sankar, Venkat; Notarbartolo, Samuele; Buenrostro, Jason D; Sallusto, Federica; Patsopoulos, Nikolaos A; Rozenblatt-Rosen, Orit; Kuchroo, Vijay K; Regev, Aviv.
  • Thakore PI; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Schnell A; Genentech, South San Francisco, CA, USA.
  • Huang L; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Zhao M; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Hou Y; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
  • Christian E; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Zaghouani S; Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.
  • Wang C; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA.
  • Singh V; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Singaraju A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Krishnan RK; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Kozoriz D; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Ma S; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Sankar V; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Notarbartolo S; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Buenrostro JD; Department of Immunology, University of Toronto and Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada.
  • Sallusto F; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Patsopoulos NA; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Rozenblatt-Rosen O; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Kuchroo VK; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Regev A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nat Immunol ; 25(8): 1395-1410, 2024 Aug.
Article en En | MEDLINE | ID: mdl-39009838
ABSTRACT
Interleukin-17 (IL-17)-producing helper T (TH17) cells are heterogenous and consist of nonpathogenic TH17 (npTH17) cells that contribute to tissue homeostasis and pathogenic TH17 (pTH17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying TH17 heterogeneity and discover substantial differences in the chromatin landscape of npTH17 and pTH17 cells both in vitro and in vivo. Compared to other CD4+ T cell subsets, npTH17 cells share accessible chromatin configurations with regulatory T cells, whereas pTH17 cells exhibit features of both npTH17 cells and type 1 helper T (TH1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating TH17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npTH17 programs and restrains proinflammatory TH1-like programs in TH17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of TH17 heterogeneity as potential targets to mitigate autoimmunity.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Cromatina / Factores de Transcripción con Cremalleras de Leucina de Carácter Básico / Células Th17 Límite: Animals / Female / Humans Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Cromatina / Factores de Transcripción con Cremalleras de Leucina de Carácter Básico / Células Th17 Límite: Animals / Female / Humans Idioma: En Año: 2024 Tipo del documento: Article