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 1

Members of PRC1 and PRC2 complexes are highly enriched at ATAC peaks associated with Crohn’s disease-related genes.

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Members of PRC1 and PRC2 complexes are highly enriched at ATAC peaks ass...
(A) Average binding profiles representing open chromatin state at ATAC peaks associated with Crohn’s disease–related genes in in vitro–generated Tregs derived from PBMCs. ATAC regions are shown to be significantly more open in Treg cells compared with T-naive cells at day 7. (B) Enrichment scores of members of PRC1 and PRC2 at ATAC peaks associated with disease-related genes from ENCODE ChIP-Seq data sets calculated using the ReMAP tool. (C) Heat map depicting PRC1 differentially regulated genes in T cells from Crohn’s patients compared with healthy individuals (>1.5 fold change, 76 genes) assessed by RNA sequencing from CD4+ T cells isolated from terminal ileum resections and enriched within known PRC1 targets. Upregulation is presented in red and downregulation in blue with intensity correlating to log fold change. (D) Chromatin immunoprecipitation with genetic knockdown of BMI1 (red) or EZH2 (blue) in Jurkat cells showing global disruption of H3K27me3 at the TSS compared with scramble (green). (E) Increase in H3K27ac marks in the absence of BMI1 (red) compared with EZH2 (blue) and scramble (green).