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

Olga F. Sarmento, Phyllis A. Svingen, Yuning Xiong, Zhifu D Sun, Adebowale O. Bamidele, Angela J. Mathison, Thomas Christopher Smyrk, Asha A. Nair, Michelle M. Gonzalez, Mary R. Sagstetter, Saurabh Baheti, Dermot P B McGovern, Jessica J. Friton, Konstantinos Papadakis, Goel Gautam, Ramnik J. Xavier, Raul A. Urrutia, William Alvis Faubion

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)706-722
Number of pages17
JournalJournal of Biological Chemistry
Volume292
Issue number2
DOIs
StatePublished - Jan 13 2017

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T-cells
Inflammatory Bowel Diseases
Genes
Regulatory T-Lymphocytes
Gene Regulatory Networks
T-Lymphocytes
Deregulation
Electric network analysis
Crohn Disease
Transcription Factors
Cells
histone methyltransferase
Enhancer of Zeste Homolog 2 Protein
RNA
Cytokines
RNA Sequence Analysis
Phenotype
Self Tolerance
Autoimmunity
Inflammation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD). / Sarmento, Olga F.; Svingen, Phyllis A.; Xiong, Yuning; Sun, Zhifu D; Bamidele, Adebowale O.; Mathison, Angela J.; Smyrk, Thomas Christopher; Nair, Asha A.; Gonzalez, Michelle M.; Sagstetter, Mary R.; Baheti, Saurabh; McGovern, Dermot P B; Friton, Jessica J.; Papadakis, Konstantinos; Gautam, Goel; Xavier, Ramnik J.; Urrutia, Raul A.; Faubion, William Alvis.

In: Journal of Biological Chemistry, Vol. 292, No. 2, 13.01.2017, p. 706-722.

Research output: Contribution to journalArticle

Sarmento, OF, Svingen, PA, Xiong, Y, Sun, ZD, Bamidele, AO, Mathison, AJ, Smyrk, TC, Nair, AA, Gonzalez, MM, Sagstetter, MR, Baheti, S, McGovern, DPB, Friton, JJ, Papadakis, K, Gautam, G, Xavier, RJ, Urrutia, RA & Faubion, WA 2017, 'The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD)', Journal of Biological Chemistry, vol. 292, no. 2, pp. 706-722. https://doi.org/10.1074/jbc.M116.749663
Sarmento, Olga F. ; Svingen, Phyllis A. ; Xiong, Yuning ; Sun, Zhifu D ; Bamidele, Adebowale O. ; Mathison, Angela J. ; Smyrk, Thomas Christopher ; Nair, Asha A. ; Gonzalez, Michelle M. ; Sagstetter, Mary R. ; Baheti, Saurabh ; McGovern, Dermot P B ; Friton, Jessica J. ; Papadakis, Konstantinos ; Gautam, Goel ; Xavier, Ramnik J. ; Urrutia, Raul A. ; Faubion, William Alvis. / The Role of the Histone Methyltransferase Enhancer of Zeste Homolog 2 (EZH2) in the Pathobiological Mechanisms Underlying Inflammatory Bowel Disease (IBD). In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 2. pp. 706-722.
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AU - Svingen, Phyllis A.

AU - Xiong, Yuning

AU - Sun, Zhifu D

AU - Bamidele, Adebowale O.

AU - Mathison, Angela J.

AU - Smyrk, Thomas Christopher

AU - Nair, Asha A.

AU - Gonzalez, Michelle M.

AU - Sagstetter, Mary R.

AU - Baheti, Saurabh

AU - McGovern, Dermot P B

AU - Friton, Jessica J.

AU - Papadakis, Konstantinos

AU - Gautam, Goel

AU - Xavier, Ramnik J.

AU - Urrutia, Raul A.

AU - Faubion, William Alvis

PY - 2017/1/13

Y1 - 2017/1/13

N2 - 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.

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