BMI1 maintains the Treg epigenomic landscape to prevent inflammatory bowel disease
Michelle M. Gonzalez, Adebowale O. Bamidele, Phyllis A. Svingen, Mary R. Sagstetter, Thomas C. Smyrk, Joseph M. Gaballa, Feda H. Hamdan, Robyn Laura Kosinsky, Hunter R. Gibbons, Zhifu Sun, Zhenqing Ye, Asha Nair, Guilherme P. Ramos, Manuel B. Braga Neto, Alexander Q. Wixom, Angela J. Mathison, Steven A. Johnsen, Raul Urrutia, William A. Faubion Jr.
Michelle M. Gonzalez, Adebowale O. Bamidele, Phyllis A. Svingen, Mary R. Sagstetter, Thomas C. Smyrk, Joseph M. Gaballa, Feda H. Hamdan, Robyn Laura Kosinsky, Hunter R. Gibbons, Zhifu Sun, Zhenqing Ye, Asha Nair, Guilherme P. Ramos, Manuel B. Braga Neto, Alexander Q. Wixom, Angela J. Mathison, Steven A. Johnsen, Raul Urrutia, William A. Faubion Jr.
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Research Article Autoimmunity Gastroenterology

BMI1 maintains the Treg epigenomic landscape to prevent inflammatory bowel disease

Abstract

FOXP3+ Tregs are expanded within the inflamed intestine of human Crohn’s disease, yet FOXP3-mediated gene repression within these cells is lost. The polycomb repressive complexes play a role in FOXP3 target gene regulation, but deeper mechanistic insight is incomplete. We have now specifically identified the polycomb-repressive complex 1 (PRC1) family member, BMI1 in the regulation of a proinflammatory enhancer network in both human and murine Tregs. Using human Tregs and lamina propria T cells, we inferred PRC1 to regulate Crohn’s associated gene networks through assays of chromatin accessibility. Conditional deletion of BMI1 in murine FOXP3+ cells led to systemic inflammation. BMI1-deficient Tregs beared a TH1/TH17-like phenotype as assessed by assays of genome wide transcription, chromatin accessibility and proteomic techniques. Finally, BMI1 mutant FOXP3+ cells did not suppress colitis in the adoptive transfer model of human inflammatory bowel disease. We propose that BMI1 plays an important role in enforcing Treg identity in vitro and in vivo. Loss of Treg identity via genetic or transient BMI1 depletion perturbs the epigenome and converts Tregs into Th1/Th17-like proinflammatory cells, a transition relevant to human Crohn’s disease associated CD4+ T cells.

Authors

Michelle M. Gonzalez, Adebowale O. Bamidele, Phyllis A. Svingen, Mary R. Sagstetter, Thomas C. Smyrk, Joseph M. Gaballa, Feda H. Hamdan, Robyn Laura Kosinsky, Hunter R. Gibbons, Zhifu Sun, Zhenqing Ye, Asha Nair, Guilherme P. Ramos, Manuel B. Braga Neto, Alexander Q. Wixom, Angela J. Mathison, Steven A. Johnsen, Raul Urrutia, William A. Faubion Jr.

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Figure 3

Characterization of conditional BMI1-deficient mice reveals a proinflammatory phenotype.

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Characterization of conditional BMI1-deficient mice reveals a proinflamm...
(A) Representative IB analysis for BMI1 protein expression in Tregs isolated from the BMI1Δ/ΔFOXP3+GFP+ or WT mouse. (B) Flow cytometric analysis of peripheral CD4+ T cells showing a higher percentage of effector (CD62Llo CD44int) and memory (CD62Llo CD44hi) T cells relative to naive (CD62Lhi) undifferentiated T cells (13.64% ± 2.429% of total CD4+ T cells vs. 6.618% ± 1.373%, P = 0.03). (C) Cytokine analysis from peripheral blood shows an increased concentration of TNF-α (27.4 pg/dL ± 10.9 vs. 10.3 ± 3.8 pg/dL, P = 0.004), IFN-γ (127.6 pg/dL ± 87.2 vs. 8.0 ± 3.6 pg/dL, P = 0.002), and IL-17 (38.9 pg/dL ± 15.6 vs. 19.2 ± 7.3 pg/dL, P = 0.04) in conditional BMI-deficient mice. (D) Histopathology from colonic samples shows increased number and size of lymphoid aggregates of the conditional BMI1-deficient mice. Data for serum cytokine analysis are from 6 biological replicates (unique animals). Error bars denote SD. Nonparametric unpaired t test was performed using Mann-Whitney U test, and P < 0.05 was considered statistically significant. *P < 0.05 and **P < 0.01.