title: The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD).
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.
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Olga F
authors.initials: OF
authors.lastname: Sarmento
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Svingen
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Yuning
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Division of Biomedical Statistics and Informatics, and.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Adebowale O
authors.initials: AO
authors.lastname: Bamidele
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Angela J
authors.initials: AJ
authors.lastname: Mathison
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Smyrk
authors.affiliation: Division of Biomedical Statistics and Informatics, and.
authors.forename: Asha A
authors.initials: AA
authors.lastname: Nair
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Gonzalez
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Mary R
authors.initials: MR
authors.lastname: Sagstetter
authors.affiliation: Division of Biomedical Statistics and Informatics, and.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Baheti
authors.affiliation: the F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Hospital, Los Angeles, California 90048.
authors.forename: Dermot P B
authors.initials: DP
authors.lastname: McGovern
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Friton
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Konstantinos A
authors.initials: KA
authors.lastname: Papadakis
authors.affiliation: the Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, and.|the Center for Computational and Integrative Biology, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Goel
authors.initials: G
authors.lastname: Gautam
authors.affiliation: the Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, and.|the Center for Computational and Integrative Biology, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine.
authors.forename: Raul A
authors.initials: RA
authors.lastname: Urrutia
authors.affiliation: From the Epigenetics and Chromatin Dynamics Laboratory, Division of Gastroenterology and Hepatology and Translational Epigenomic Program, Center for Individualized Medicine, Faubion.william@mayo.edu.
authors.forename: William A
authors.initials: WA
authors.lastname: Faubion
mesh_terms: D000818:Animals; D003424:Crohn Disease / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D053263:Gene Regulatory Networks / Q000276:immunology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse
keywords: Crohn's disease; EZH2; T helper cells; epigenetics; forkhead box P3 (FOXP3); histone methylation; inflammatory bowel disease (IBD); regulatory T cell; transcriptional corepressor