403

EPIGENETIC SILENCING OF A LATENT TH17-LIKE PROGRAM IN HUMAN TREGS

Date
May 19, 2024

Background: Loss of the suppressive function of helper T regulatory cells (Tregs) can promote uncontrolled inflammation in Crohn’s Disease (CD). We have previously shown that Tregs of CD patients aberrantly express proinflammatory genes downstream of TNFα signaling, but the mechanisms that regulate this transcriptional change in Tregs of CD patients remain unknown. Distinct chromatin landscapes in human T helper cells were recently reported to regulate gene programs such as tissue repair and pathogenicity. Therefore, targeting chromatin-based features controlling transcription in Tregs could revolutionize CD therapy. The aim of this study was to identify an actionable target to sustain Treg suppressive function and control inflammation in CD.
Methods: To identify upstream regulators of Treg dysfunction, we used a multiomic approach including RNA-seq and assay for transposase-accessible chromatin (ATAC-seq) in different stages of differentiation of Tregs and proinflammatory Th17 cells. We used multiple bioinformatic pipelines to identify epigenetic factors that drive the activation of open chromatin regions associated with proinflammatory gene networks in Tregs. We then validated the enrichment of these factors at these regions by Chromatin immunoprecipitation (ChIP-seq). CRISPR-mediated gene editing in primary human Tregs was performed to test the effect of targeting these factors on sustaining Treg function in the presence of inflammatory stimuli such as TNFα.
Results: We identified open chromatin regions in late-stage differentiated Tregs that are predominantly activated in early-stage differentiation of the proinflammatory Th17 cells. Characterization of gene networks associated with these regions uncovered multiple proinflammatory gene programs that are expressed in Th17 but not expressed in functional Tregs at any differentiation stage. We found that when these regions are inactive during the early stages of Tregs differentiation, TNFα does not affect their activity or the expression of the associated genes. However, it increases the enrichment of the epigenetic regulator, Bromodomain containing protein 4 (BRD4). Knockout of BRD4 in Tregs decreased the activation of proinflammatory genes in Tregs.
Conclusions: This study identifies a proinflammatory Th17-like chromatin landscape that is actively silenced in functional Tregs. Aberrant activation of this program can attenuate Treg function and perpetuate uncontrolled inflammation in CD patients. In this study, we uncover an actionable target (BRD4) to sustain the silencing of the Th17-like program with the goal of controlling inflammation in CD patients.

Tracks

Related Products

Thumbnail for VALIDATION OF COPY NUMBER ABERRATION AND METHYLATED DNA MARKERS FOR DIFFERENTIATION OF NON-DYSPLASTIC BARRETT’S ESOPHAGUS FROM BARRETT’S ESOPHAGUS WITH HIGH GRADE DYSPLASIA AND ESOPHAGEAL ADENOCARCINOMA : A MULTICENTER STUDY
VALIDATION OF COPY NUMBER ABERRATION AND METHYLATED DNA MARKERS FOR DIFFERENTIATION OF NON-DYSPLASTIC BARRETT’S ESOPHAGUS FROM BARRETT’S ESOPHAGUS WITH HIGH GRADE DYSPLASIA AND ESOPHAGEAL ADENOCARCINOMA : A MULTICENTER STUDY
Endoscopic surveillance of Barrett’s esophagus (BE) is recommended to identify dysplasia (low grade [LGD], high grade [HGD]) or adenocarcinoma [EAC]) for endoscopic intervention. However, this paradigm is limited by sampling error and subtle endoscopic changes, leading to missed HGD and EAC…
Thumbnail for NOVEL PLATFORMS FOR IDENTIFYING AND TESTING SMALL MOLECULE DRUG BASED TREATMENTS FOR INFLAMMATORY BOWEL DISEASE.
NOVEL PLATFORMS FOR IDENTIFYING AND TESTING SMALL MOLECULE DRUG BASED TREATMENTS FOR INFLAMMATORY BOWEL DISEASE.
BACKGROUND: Tofacitinib and upadacitinib are JAK inhibitors (JAKi) approved for Inflammatory Bowel Disease (IBD) treatment. Response rates to JAKi in IBD are varied, and there are concerns for serious side effects like venous thromboembolism, cancer and cardiovascular events…
Thumbnail for INSPIRE: PRELIMINARY DATA FROM AN OBSERVATIONAL POST-MARKETING REGISTRY ON THE EFFECTIVENESS AND SAFETY OF DARVADSTROCEL IN PATIENTS WITH CROHN’S DISEASE AND COMPLEX PERIANAL FISTULAS
INSPIRE: PRELIMINARY DATA FROM AN OBSERVATIONAL POST-MARKETING REGISTRY ON THE EFFECTIVENESS AND SAFETY OF DARVADSTROCEL IN PATIENTS WITH CROHN’S DISEASE AND COMPLEX PERIANAL FISTULAS
BACKGROUND: Darvadstrocel (DVS), a suspension of expanded allogeneic adipose-derived mesenchymal stem cells, is approved for the treatment of complex Crohn’s perianal fistulas (CPF)…
Thumbnail for MECHANOGATED ION CHANNEL PIEZO2 TETHERS TO THE ACTOMYOSIN CYTOSKELETON IN INTESTINAL EPITHELIAL MECHANORECEPTORS
MECHANOGATED ION CHANNEL PIEZO2 TETHERS TO THE ACTOMYOSIN CYTOSKELETON IN INTESTINAL EPITHELIAL MECHANORECEPTORS
BACKGROUND The gastrointestinal tract (GI) has a sense of _gut touch_ by which low threshold mechanical inputs activate mechanoreceptors similar to Merkel cells that mediate skin touch…