{"doi":"10.1016/j.jbc.2022.101616","title":"Regulatory domains controlling high intestinal vitamin D receptor gene expression are conserved in mouse and human","abstract":"Vitamin D receptor (VDR) levels are highest in the intestine where it mediates 1,25 dihydroxyvitamin D-induced gene expression. However, the mechanisms controlling high intestinal VDR gene expression are unknown. Here, we used Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq) to identify the regulatory sites controlling intestine-specific Vdr gene expression in the small intestine (villi and crypts) and colon of developing, adult, and aged mice. We identified 17 ATAC peaks in a 125 kb region from intron 3 to −55.8 kb from exon 1 of the Vdr gene. Interestingly, many of these peaks were missing/reduced in the developing intestine. Chromatin ImmunoPrecipitation-Sequencing (ChIP-Seq) peaks for intestinal transcription factors (TFs) were present within the ATAC peaks and at HiChIP looping attachments that connected the ATAC/TF ChIP peaks to the transcription start site and CCCTF-binding factor sites at the borders of the Vdr gene regulatory domain. Intestine-specific regulatory sites were identified by comparing ATAC peaks to DNAse-Seq data from other tissues that revealed tissue-specific, evolutionary conserved, and species-specific peaks. Bioinformatics analysis of human DNAse-Seq peaks revealed polymorphisms that disrupt TF-binding sites. Our analysis shows that mouse intestinal Vdr gene regulation requires a complex interaction of multiple distal regulatory regions and is controlled by a combination of intestinal TFs. These intestinal regulatory sites are well conserved in humans suggesting that they may be key components of VDR regulation in both mouse and human intestines. Vitamin D receptor (VDR) levels are highest in the intestine where it mediates 1,25 dihydroxyvitamin D-induced gene expression. However, the mechanisms controlling high intestinal VDR gene expression are unknown. Here, we used Assay for Transposase-Accessible Chromatin using Sequencing (ATAC-Seq) to identify the regulatory sites controlling intestine-specific Vdr gene expression in the small intestine (villi and crypts) and colon of developing, adult, and aged mice. We identified 17 ATAC peaks in a 125 kb region from intron 3 to −55.8 kb from exon 1 of the Vdr gene. Interestingly, many of these peaks were missing/reduced in the developing intestine. Chromatin ImmunoPrecipitation-Sequencing (ChIP-Seq) peaks for intestinal transcription factors (TFs) were present within the ATAC peaks and at HiChIP looping attachments that connected the ATAC/TF ChIP peaks to the transcription start site and CCCTF-binding factor sites at the borders of the Vdr gene regulatory domain. Intestine-specific regulatory sites were identified by comparing ATAC peaks to DNAse-Seq data from other tissues that revealed tissue-specific, evolutionary conserved, and species-specific peaks. Bioinformatics analysis of human DNAse-Seq peaks revealed polymorphisms that disrupt TF-binding sites. Our analysis shows that mouse intestinal Vdr gene regulation requires a complex interaction of multiple distal regulatory regions and is controlled by a combination of intestinal TFs. These intestinal regulatory sites are well conserved in humans suggesting that they may be key components of VDR regulation in both mouse and human intestines. Vitamin D is a nutrient that serves as the precursor for 1,25 dihydroxyvitamin D (1,25(OH)2D), a hormone that controls a wide variety of biological processes relevant to human health (1Norman A.W. From vitamin D to hormone D: Fundamentals of the vitamin D endocrine system essential for good health.Am. J. Clin. Nutr. 2008; 88: 491S-499SGoogle Scholar). The actions of 1,25(OH)2D are mediated through the induction of gene transcription following activation of the vitamin D receptor (VDR)—a ligand-activated transcription factor (TF) (2Pike J.W. Christakos S. Biology and mechanisms of action of the vitamin D hormone.Endocrinol. Metab. Clin. North Am. 2017; 46: 815-843Google Scholar) The most studied action of vitamin D is the control of intestinal cal","journal":"Journal of Biological Chemistry","year":2022,"id":269884,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":14,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":697082,"name":"Dennis Aldea","orcid":"0000-0002-0809-6030","position":1,"is_corresponding":false},{"id":506485,"name":"Lei Chen","orcid":"0000-0001-7812-508X","position":2,"is_corresponding":false},{"id":371187,"name":"Sylvia Christakos","orcid":"0000-0001-9148-5549","position":3,"is_corresponding":false},{"id":241177,"name":"Michael P. Verzi","orcid":"0000-0003-4082-4330","position":4,"is_corresponding":false},{"id":371186,"name":"James C. Fleet","orcid":"0000-0002-0142-9517","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-19T00:27:22.602796Z","pmid":"35065959","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}