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 4

BMI1 knockdown specifically upregulates H3K27ac occupancy at TSS of regulated genes and is relevant to human CD.

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BMI1 knockdown specifically upregulates H3K27ac occupancy at TSS of regu...
(A) Splenic Tregs isolated from conditional BMI1 KO mice showed expression of proinflammatory cytokines TNF-α (18.9 pg/dL ± 12.3 vs. 6.7 ± 1.0 pg/dL, P = 0.029) and IFN-γ (70.9 ± 67.6 pg/dL vs. 4.9 ± 2.9 pg/dL, P = 0.029) by multiplex cytokine analysis. (B) Principal component analysis separates BMI1–/– FOXP3+ cells (red) from WT (blue) Tregs (data representative of 5 mice/condition in 2 separate experiments). (C) Upregulated (red) and downregulated (green) differentially expressed genes that separate murine BMI1–/– FOXP3+ cells from WT Tregs. (D) Gene ontology analysis (GO Biological Process 2018b) of the 130 upregulated genes identified in resting BMI1–/– FOXP3+ compared with WT Tregs (Enrichr, Ma’ayan Lab). (E) Average occupancy profiles of H3K27ac in Jurkat cells at TSS of human homologs of genes upregulated in BMIKO mice. (F) Violin plots demonstrating enrichment of 12 BMI1KO genes within the Treg-specific scRNAseq data derived from patients with Crohn’s disease displaying a GIMATS phenotype. The data for the cytokines are generated from n = 4 animals, in triplicates. Nonparametric unpaired t test was performed using Mann-Whitney U test, and P < 0.05 was considered statistically significant. Numerical values reflecting means ± standard deviation. Means obtained from average in triplicates from each mouse. Error bars denote SEM.