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J Biol Chem. 2017 Jan 13;292(2):706-722. doi: 10.1074/jbc.M116.749663. Epub 2016 Dec 1.

The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD).

Author information

1
From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
2
Division of Biomedical Statistics and Informatics, and.
3
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905.
4
the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Hospital, Los Angeles, California 90048.
5
the Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, and.
6
the Center for Computational and Integrative Biology, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142.
7
From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine, Faubion.william@mayo.edu.

Abstract

Regulatory T (Treg) cells expressing the transcription factor FOXP3 play a pivotal role in maintaining immunologic self-tolerance. We and others have shown previously that EZH2 is recruited to the FOXP3 promoter and its targets in Treg cells. To further address the role for EZH2 in Treg cellular function, we have now generated mice that lack EZH2 specifically in Treg cells (EZH2Δ/ΔFOXP3+). We find that EZH2 deficiency in FOXP3+ T cells results in lethal multiorgan autoimmunity. We further demonstrate that EZH2Δ/ΔFOXP3+ T cells lack a regulatory phenotype in vitro and secrete proinflammatory cytokines. Of special interest, EZH2Δ/ΔFOXP3+ mice develop spontaneous inflammatory bowel disease. Guided by these results, we assessed the FOXP3 and EZH2 gene networks by RNA sequencing in isolated intestinal CD4+ T cells from patients with Crohn's disease. Gene network analysis demonstrates that these CD4+ T cells display a Th1/Th17-like phenotype with an enrichment of gene targets shared by FOXP3 and EZH2. Combined, these results suggest that the inflammatory milieu found in Crohn's disease could lead to or result from deregulation of FOXP3/EZH2-enforced T cell gene networks contributing to the underlying intestinal inflammation.

KEYWORDS:

Crohn's disease; EZH2; T helper cells; epigenetics; forkhead box P3 (FOXP3); histone methylation; inflammatory bowel disease (IBD); regulatory T cell; transcriptional corepressor

PMID:
27909059
PMCID:
PMC5241744
DOI:
10.1074/jbc.M116.749663
[Indexed for MEDLINE]
Free PMC Article

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