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Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation
Frann Antignano, … , Megan K. Levings, Colby Zaph
Frann Antignano, … , Megan K. Levings, Colby Zaph
Published March 25, 2014
Citation Information: J Clin Invest. 2014;124(5):1945-1955. https://doi.org/10.1172/JCI69592.
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Research Article Immunology

Methyltransferase G9A regulates T cell differentiation during murine intestinal inflammation

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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

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

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Figure 1

G9A is required for the development of experimental colitis.

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G9A is required for the development of experimental colitis.
CD4+CD25–CD...
CD4+CD25–CD45RBhi naive T cells (4 × 105) from G9afl/fl or G9a–/– mice were transferred into Rag1–/– mice and monitored for colitis. (A) Weight loss (percentage of initial weight) was calculated for each mouse over 7 weeks. (B) Representative sections of H&E-stained proximal colons. Scale bars: 100 μm. (C) Colitis was assessed histologically at 7 weeks after transfer, and severity of inflammation was scored. (D) Colon length, (E) spleen weight and cellularity, and (F) serum TNF-α were analyzed at 7 weeks after transfer. (G) Frequency and total number of CD4+ T cells in spleen and mLN. Each point represents an individual mouse, and the data are from 2 of 4 independent experiments (n = 5–8 per experiment). Statistics compare Rag1–/– mice that received G9afl/fl T cells to those that received G9a–/– T cells. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars indicate SEM.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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