title: Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation.
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.
authors.forename: Frann
authors.initials: F
authors.lastname: Antignano
authors.forename: Kyle
authors.initials: K
authors.lastname: Burrows
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hughes
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Han
authors.forename: Ken J
authors.initials: KJ
authors.lastname: Kron
authors.forename: Nadia M
authors.initials: NM
authors.lastname: Penrod
authors.forename: Menno J
authors.initials: MJ
authors.lastname: Oudhoff
authors.forename: Steven Kai Hao
authors.initials: SK
authors.lastname: Wang
authors.forename: Paul H
authors.initials: PH
authors.lastname: Min
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Gold
authors.forename: Alistair L
authors.initials: AL
authors.lastname: Chenery
authors.forename: Mitchell J S
authors.initials: MJ
authors.lastname: Braam
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Fung
authors.forename: Fabio M V
authors.initials: FM
authors.lastname: Rossi
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McNagny
authors.forename: Cheryl H
authors.initials: CH
authors.lastname: Arrowsmith
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lupien
authors.forename: Megan K
authors.initials: MK
authors.lastname: Levings
authors.forename: Colby
authors.initials: C
authors.lastname: Zaph
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002843:Chromatin / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006649:Histocompatibility Antigens / Q000235:genetics / Q000276:immunology; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D006657:Histones / Q000235:genetics / Q000276:immunology; D008745:Methylation / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology
chemical_list: D002843:Chromatin; D004791:Enzyme Inhibitors; D006649:Histocompatibility Antigens; D006657:Histones; D053773:Transforming Growth Factor beta1; C445405:EHMT2 protein, human; C533711:G9a protein, mouse; D011495:Histone-Lysine N-Methyltransferase