RNF20 and RNF40 regulate vitamin D receptor-dependent signaling in inflammatory bowel disease

Robyn Laura Kosinsky, Maria Zerche, Ana Patricia Kutschat, Asha Nair, Zhenqing Ye, Dominik Saul, Maximilian von Heesen, Jessica J. Friton, Ana Carolina Schwarzer, Nadia Paglilla, Shehzad Z. Sheikh, Florian Wegwitz, Zhifu Sun, Michael Ghadimi, Rodney D. Newberry, R. Balfour Sartor, William A. Faubion, Steven A. Johnsen

Research output: Contribution to journalArticlepeer-review

Abstract

Despite the identification of several genetic factors linked to increased susceptibility to inflammatory bowel disease (IBD), underlying molecular mechanisms remain to be elucidated in detail. The ubiquitin ligases RNF20 and RNF40 mediate the monoubiquitination of histone H2B at lysine 120 (H2Bub1) and were shown to play context-dependent roles in the development of inflammation. Here, we aimed to examine the function of the RNF20/RNF40/H2Bub1 axis in intestinal inflammation in IBD patients and mouse models. For this purpose, intestinal sections from IBD patients were immunohistochemically stained for H2Bub1. Rnf20 or Rnf40 were conditionally deleted in the mouse intestine and mice were monitored for inflammation-associated symptoms. Using mRNA-seq and chromatin immunoprecipitation (ChIP)-seq, we analyzed underlying molecular pathways in primary intestinal epithelial cells (IECs) isolated from these animals and confirmed these findings in IBD resection specimens using ChIP-seq.The majority (80%) of IBD patients displayed a loss of H2Bub1 levels in inflamed areas and the intestine-specific deletion of Rnf20 or Rnf40 resulted in spontaneous colorectal inflammation in mice. Consistently, deletion of Rnf20 or Rnf40 promoted IBD-associated gene expression programs, including deregulation of various IBD risk genes in these animals. Further analysis of murine IECs revealed that H3K4me3 occupancy and transcription of the Vitamin D Receptor (Vdr) gene and VDR target genes is RNF20/40-dependent. Finally, these effects were confirmed in a subgroup of Crohn’s disease patients which displayed epigenetic and expression changes in RNF20/40-dependent gene signatures. Our findings reveal that loss of H2B monoubiquitination promotes intestinal inflammation via decreased VDR activity thereby identifying RNF20 and RNF40 as critical regulators of IBD.

Original languageEnglish (US)
JournalCell Death and Differentiation
DOIs
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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