{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Kolev HM"],"funding":["NIDDK NIH HHS","National Institutes of Health"],"pagination":["821-839"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9971508"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(4)"],"pubmed_abstract":["<h4>Background & aims</h4>Although trimethylation of histone H3 lysine 27 (H3K27me3) by polycomb repressive complex 2 is required for intestinal function, the role of the antagonistic process-H3K27me3 demethylation-in the intestine remains unknown. The aim of this study was to determine the contribution of H3K27me3 demethylases to intestinal homeostasis.<h4>Methods</h4>An inducible mouse model was used to simultaneously ablate the 2 known H3K27me3 demethylases, lysine (K)-specific demethylase 6A (Kdm6a) and lysine (K)-specific demethylase 6B (Kdm6b), from the intestinal epithelium. Mice were analyzed at acute and prolonged time points after Kdm6a/b ablation. Cellular proliferation and differentiation were measured using immunohistochemistry, while RNA sequencing and chromatin immunoprecipitation followed by sequencing for H3K27me3 were used to identify gene expression and chromatin changes after Kdm6a/b loss. Intestinal epithelial renewal was evaluated using a radiation-induced injury model, while Paneth cell homeostasis was measured via immunohistochemistry, immunoblot, and transmission electron microscopy.<h4>Results</h4>We did not detect any effect of Kdm6a/b ablation on intestinal cell proliferation or differentiation toward the secretory cell lineages. Acute and prolonged Kdm6a/b loss perturbed expression of gene signatures belonging to multiple cell lineages (adjusted P value < .05), and a set of 72 genes was identified as being down-regulated with an associated increase in H3K27me3 levels after Kdm6a/b ablation (false discovery rate, <0.05). After prolonged Kdm6a/b loss, dysregulation of the Paneth cell gene signature was associated with perturbed matrix metallopeptidase 7 localization (P < .0001) and expression.<h4>Conclusions</h4>Although KDM6A/B does not regulate intestinal cell differentiation, both enzymes are required to support the full transcriptomic and epigenomic landscape of the intestinal epithelium and the expression of key Paneth cell genes."],"journal":["Cellular and molecular gastroenterology and hepatology"],"pubmed_title":["H3K27me3 Demethylases Maintain the Transcriptional and Epigenomic Landscape of the Intestinal Epithelium."],"pmcid":["PMC9971508"],"funding_grant_id":["P30 DK019525","K01 DK116922","R37 DK053839","P30 DK050306","F31 DK126404"],"pubmed_authors":["Kolev HM","Kaestner KH","Swisa A","Testa G","Stine RR","Manduchi E","Lan Y"],"additional_accession":[]},"is_claimable":false,"name":"H3K27me3 Demethylases Maintain the Transcriptional and Epigenomic Landscape of the Intestinal Epithelium.","description":"<h4>Background & aims</h4>Although trimethylation of histone H3 lysine 27 (H3K27me3) by polycomb repressive complex 2 is required for intestinal function, the role of the antagonistic process-H3K27me3 demethylation-in the intestine remains unknown. The aim of this study was to determine the contribution of H3K27me3 demethylases to intestinal homeostasis.<h4>Methods</h4>An inducible mouse model was used to simultaneously ablate the 2 known H3K27me3 demethylases, lysine (K)-specific demethylase 6A (Kdm6a) and lysine (K)-specific demethylase 6B (Kdm6b), from the intestinal epithelium. Mice were analyzed at acute and prolonged time points after Kdm6a/b ablation. Cellular proliferation and differentiation were measured using immunohistochemistry, while RNA sequencing and chromatin immunoprecipitation followed by sequencing for H3K27me3 were used to identify gene expression and chromatin changes after Kdm6a/b loss. Intestinal epithelial renewal was evaluated using a radiation-induced injury model, while Paneth cell homeostasis was measured via immunohistochemistry, immunoblot, and transmission electron microscopy.<h4>Results</h4>We did not detect any effect of Kdm6a/b ablation on intestinal cell proliferation or differentiation toward the secretory cell lineages. Acute and prolonged Kdm6a/b loss perturbed expression of gene signatures belonging to multiple cell lineages (adjusted P value < .05), and a set of 72 genes was identified as being down-regulated with an associated increase in H3K27me3 levels after Kdm6a/b ablation (false discovery rate, <0.05). After prolonged Kdm6a/b loss, dysregulation of the Paneth cell gene signature was associated with perturbed matrix metallopeptidase 7 localization (P < .0001) and expression.<h4>Conclusions</h4>Although KDM6A/B does not regulate intestinal cell differentiation, both enzymes are required to support the full transcriptomic and epigenomic landscape of the intestinal epithelium and the expression of key Paneth cell genes.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023","modification":"2025-04-19T02:43:40.937Z","creation":"2025-02-19T04:54:53.373Z"},"accession":"S-EPMC9971508","cross_references":{"pubmed":["36503150"],"doi":["10.1016/j.jcmgh.2022.12.001"]}}