Faculty Collaboration Database

The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD). J Biol Chem 2017 Jan 13;292(2):706-722

Date

12/03/2016

Pubmed ID

27909059

Pubmed Central ID

PMC5241744

DOI

10.1074/jbc.M116.749663

Scopus ID

2-s2.0-85009804809 (requires institutional sign-in at Scopus site)   58 Citations

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 (EZH2^Δ/ΔFOXP3⁺). We find that EZH2 deficiency in FOXP3⁺ T cells results in lethal multiorgan autoimmunity. We further demonstrate that EZH2^Δ/ΔFOXP3⁺ T cells lack a regulatory phenotype in vitro and secrete proinflammatory cytokines. Of special interest, EZH2^Δ/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.

Author List

Sarmento OF, Svingen PA, Xiong Y, Sun Z, Bamidele AO, Mathison AJ, Smyrk TC, Nair AA, Gonzalez MM, Sagstetter MR, Baheti S, McGovern DP, Friton JJ, Papadakis KA, Gautam G, Xavier RJ, Urrutia RA, Faubion WA

Authors

Angela Mathison PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Crohn Disease
Cytokines
Enhancer of Zeste Homolog 2 Protein
Forkhead Transcription Factors
Gene Regulatory Networks
Humans
Mice
Mice, Transgenic
T-Lymphocytes, Regulatory
Th17 Cells