The transcription factor FOXP3 is critical to the regulation of numerous debilitating human immune-mediated diseases. Very recently, the essential role for the histone methyltransferase (HMT) EZH2 in the epigenetic regulation and function of FOXP3 has been described. Inflammatory pathways modify EZH2 activity, and inflammatory signaling impairs Treg function in vivo and in vitro. The biological impact of the FOXP3-EZH2 pathway to IBD is unknown. Our long-term goal is to dissect epigenetic mechanisms regulating Treg cellular differentiation and function, particularly within the setting o GI inflammatory diseases. These discoveries will facilitate design of human cell therapy trials for IBD. The objective of this grant is to characterize the role for EZH2 in Treg suppressive function. The central hypothesis is that EZH2 plays a critical role in the homeostasis of Treg cells, and the disruption of EZH2 function by inflammatory signaling pathways contributes to IBD. Our rationale is that identification of the mechanism(s) to restore Treg suppressive function in the setting of intestinal inflammation will offer new therapeutic opportunities.
Our specific aims will test the following hypotheses:
(Aim1) Repression of immunoregulatory gene networks by FOXP3 requires the formation of a complex between this transcription factor and EZH2;
(Aim 2) Inflammatory stimuli, such as IL6 lead to EZH2 phosphorylation and thereby disrupt the enzymatic activity of this epigenomic regulator;
(Aim 3) Inhibition of the IL6 to EZH2 signaling pathway permits sustained Treg suppressive function in the setting of intestinal inflammation. Upon conclusion, we will understand the role for EZH2 in Treg loss of function in the setting of active inflammation. This contribution is significant since it will establish that several pathways targeted by available therapies (ie IL1?, IL6, TNF?) have the potential to regulate EZH2 HMT activity through post- translational modifications. Furthermore, current Treg cell therapy trials, while promising have not addressed the key issue of in vivo inflammation-induced disruption of Treg function. The proposed research is innovative because we investigate the effect of inflammatory signaling pathways on epigenetic complexes in Treg cells, a heretofore-unexamined process. Insight into epigenetic mechanisms is impactful as T cell progenitor cells inherit the parent transcriptional profile and unlike genetic change, they are modifiable by currently available therapy.

Public Health Relevance

The proposed research is relevant to the public health because IBD, increasing in prevalence, represents a major national cost measured by both patient suffering and economic burden; and despite significant advances in care, clinical trial data demonstrate remission rates at best of 40%. Upon conclusion, we will understand the role for EZH2 in Treg loss of function in the setting of active inflammation, and this discovery will stimulate the opening of a new avenue in therapeutics directed at stimulation of autologous Treg cells to function within the inflammatory milieu.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI089714-08
Application #
9412417
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Rothermel, Annette L
Project Start
2010-07-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Dietz, Allan B; Dozois, Eric J; Fletcher, Joel G et al. (2017) Autologous Mesenchymal Stem Cells, Applied in a Bioabsorbable Matrix, for Treatment of Perianal Fistulas in Patients With Crohn's Disease. Gastroenterology 153:59-62.e2
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Papadakis, Konstantinos A; Krempski, James; Svingen, Phyllis et al. (2015) Krüppel-like factor KLF10 deficiency predisposes to colitis through colonic macrophage dysregulation. Am J Physiol Gastrointest Liver Physiol 309:G900-9
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Okou, David T; Mondal, Kajari; Faubion, William A et al. (2014) Exome sequencing identifies a novel FOXP3 mutation in a 2-generation family with inflammatory bowel disease. J Pediatr Gastroenterol Nutr 58:561-8

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