Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation
Year: 2014
Type: article
Abstract: Inflammatory bowel disease (IBD) pathogenesis is associated with dysregulated CD4⁺ Th cell responses, with intestinal homeostasis depending on the balance between IL-17-producing Th17 and Foxp3⁺ Tregs. Differentiation of naive T cells into Th17 and Treg subsets is associated with specific gene expression profiles; however, the contribution of epigenetic mechanisms to controlling Th17 and Treg differentiation remains unclear. Using a murine T cell transfer model of colitis, we found that T cell-intrinsic expression of the histone lysine methyltransferase G9A was required for development of pathogenic T cells and intestinal inflammation. G9A-mediated dimethylation of histone H3 lysine 9 (H3K9me2) restricted Th17 and Treg differentiation in vitro and in vivo. H3K9me2 was found at high levels in naive Th cells and was lost following Th cell activation. Loss of G9A in naive T cells was associated with increased chromatin accessibility and heightened sensitivity to TGF-β1. Pharmacological inhibition of G9A methyltransferase activity in WT T cells promoted Th17 and Treg differentiation. Our data indicate that G9A-dependent H3K9me2 is a homeostatic epigenetic checkpoint that regulates Th17 and Treg responses by limiting chromatin accessibility and TGF-β1 responsiveness, suggesting G9A as a therapeutic target for treating intestinal inflammation.
DOI: 10.1172/jci69592
Authors: Frann Antignano, Kyle Burrows, Michael R. Hughes, Jonathan M. Han, Ken J. Kron, Nadia M. Penrod, Menno J. Oudhoff, Steven Kai Hao Wang, Paul H. Min, Matthew J. Gold, Alistair L. Chenery, Mitchell J.S. Braam, Thomas C. Fung, Fabio M.V. Rossi, Kelly M. McNagny, Cheryl H. Arrowsmith, Mathieu Lupien, Megan K. Levings, Colby Zaph
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Funders: Eli Lilly and Company, Pfizer, Genome Canada, Wellcome Trust, Crohn's and Colitis Foundation, Ontario Genomics, Crohn's and Colitis Foundation of Canada, Ontario Genomics Institute, Canadian Association of Gastroenterology, Ontario Ministry of Economic Development and Innovation, Michael Smith Health Research BC, Ministero dello Sviluppo Economico, Canadian Institutes of Health Research
Awards: G1485802007, G1651692390, Regulation of intestinal homeostasis and cancer by the lysine methyltransferase Set7, Open access research to promote drug discovery., G2967825847, G4089185365, G4350982294, G4836090474, CD34 in inflammatory cell migration and function, Molecular and cellular biology of T regulatory cells, G5657743773, Open access research to promote drug discovery., Role of the methyltransferase G9a in normal hematopoiesis and leukaemia, G7181266764, G774547617, G8348572397
OpenAlex ID: W2063786362