BMI1 maintains the Treg epigenomic landscape to prevent inflammatory bowel disease
Michelle M. Gonzalez, … , Raul Urrutia, William A. Faubion Jr.
Michelle M. Gonzalez, … , Raul Urrutia, William A. Faubion Jr.
Published June 15, 2021
Citation Information: J Clin Invest. 2021;131(12):e140755. https://doi.org/10.1172/JCI140755.
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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 6

BMI1-deficient Tregs fail to suppress colitis in vivo.

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BMI1-deficient Tregs fail to suppress colitis in vivo. Mice subjected to...
Mice subjected to T cell transfer model of colitis with concomitant injection of naive T cells with either BMI1–/– Tregs or WT Tregs. Mice injected with BMI1–/– Tregs had (A) stunted weight gain (1.1 ± 0.11 fold change from initial weight vs. 1.4 ± 0.05 fold change, P = 0.005) and (B) increased DAI when compared with mice injected with WT Tregs (2.6 ± 0.63 vs. 0.42 ± 0.32, P = 0.0048). The numerical values for DAI are the added product of a score calculated based appearance, stool consistency, and colon stiffness. (C) Cytokine analysis from peripheral blood showed an increased secretion of TNF-α (76.6 ± 18.8 pg/dL vs. 6.0 ± 3.2 pg/dL, P = 0.028), IFN-γ (10.0 ± 2.3 pg/dL vs. 1.2 ± 0.7 pg/dL, P = 0.028), and IL-17 (6.9 ± 3.6 pg/dL vs. 0.2 ± 0.3 pg/dL, P = 0.028) in the mice receiving the BMI-deficient Tregs. (D) Histopathology of colon specimens revealed moderate colitis in mice injected with BMI1-deficient Tregs while mice receiving WT Tregs did not have evidence of colitis (histologic scores 12.0 ± 0.82 pg/dL vs. 0 ± 0.00 pg/dL, P = 0.029). The data for the RbHi experiment are generated from n = 12 animals, 4/group. Nonparametric unpaired t test was performed using Mann-Whitney U test, and P < 0.05 was considered statistically significant. For histologic score significance, Kruskal Wallis test was used for multiple comparisons, and P < 0.05 was considered statistically significant. Numerical values reflecting means ± standard deviation. Error bars denote SEM.