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RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis.

ABSTRACT: A member of the nuclear receptors, retinoic acid-related orphan receptor a (RORa) is an important transcription factor for various biological processes including circadian rhythm, metabolic regulation, immune cell development and cancer. Here we found that RORa is important for intestinal homeostasis by negatively regulating the transcriptional activity of NF-kB, a major inflammatory regulator in intestinal epithelial cells. Intestinal Rora-deficient mice found were highly susceptible to DSS-induced injury. Transcriptome analysis showed that intestine-specific Rora deletion causes regulatory impairment of NF-kB signaling leading to excessive inflammatory responses. RORa specifically binds to the NF-kB target promoter and inhibits transcriptional activity for transcriptional repression of NF-kB activity via histone deacetylase 3 (HDAC3). Taken together, RORa plays a pivotal role in the homeostatic regulation of intestinal epithelial cells in inflammatory conditions. Therefore, therapeutic strategies designed to modulate RORa activity may be beneficial in the treatment of chronic inflammatory diseases such as Inflammatory bowel disease (IBD).

ORGANISM(S): Mus musculus

PROVIDER: GSE121977 | GEO | 2019/09/30

REPOSITORIES: GEO

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Project description:Genes encoding transcription factors function as hubs in gene regulatory networks because they encode DNA-binding proteins, which bind to promoters that carry their binding sites. In the present work we have studied gene regulatory networks defined by genes with transcripts belonging to different mRNA abundance classes in the small intestinal epithelial cell. The focus is the rewiring that occurs in transcription factor hubs in these networks during the differentiation of the small intestinal epithelial cell while it migrates along the crypt-villus axis and during its development from a fetal endodermal cell to a mature adult villus epithelial cell. We have generated transcriptome data for mouse small intestinal villus, crypt and fetal intestinal epithelial cells. In addition we have generated metabolome data from crypt and villus cells. Our results show that the intestinal crypt transcription factor hubs that are rewired during differentiation are involved in the cell cycle process (E2F, NF-Y) and stem cell maintenance (c-Myc). In contrast the villi are dominated by a HNF-4 villus hub, which is rewired during differentiation by the addition of network genes with relevance for lipoprotein synthesis and lipid absorption. Moreover, we have identified a villus NF-kB hub, which was revealed by comparison of the villus and endoderm transcriptomes. The rewiring of the NF-kB villus hub during intestinal development reflects transcriptional activity established by host and microflora interactions. To aid in the mining of our results we have developed a web portal (http://gastro.imbg.ku.dk/mousecv/) allowing easy linkage between the transcriptomic data, biological processes and functions. Experiment Overall Design: Four different sample categories were analyzed. Experiment Overall Design: 1) Small intestinal crypts isolated form 12-weeks old C57BL/6 mice. These samples are in triplicates. Experiment Overall Design: 2) Small intestinal villi isolated form 12-weeks old C57BL/6 mice. These samples are in triplicates. Experiment Overall Design: 3) Embryonic day 12 mesenchyme. These samples are in quadruplicate. each sample is derived from a pool of mesenchymes (10-40) Experiment Overall Design: 4) Embryonic day 12 endoderm. These samples are in quadruplicate. each sample is derived from a pool of endoderms (10-40)

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RORα is crucial for attenuated inflammatory response to maintain intestinal homeostasis.

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