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To address this question, we examined in vivo estrous cycle dynamics of mouse uterus hormone receptor occupancy, chromatin accessibility and chromatin structure by combining RNA-seq, ATAC-seq, HiC-seq\u00a0and ChIP-seq. Two estrous cycle stages were chosen for these analyses, diestrus (highest estrogen) and estrus (highest progesterone). Unexpectedly, rather than alternating with each other, estrogen receptor alpha (ER\u03b1) and progesterone receptor (PGR) were co-bound during diestrus and lost during estrus. Motif analysis of open chromatin followed by hypoxia inducible factor 2A (HIF2A) ChIP-seq and conditional uterine deletion of this transcription factor revealed a novel role for HIF2A in regulating diestrus gene expression patterns that were independent of either ER\u03b1 or PGR binding. Proteins in complex with ER\u03b1 included PGR and cohesin, only during diestrus. Combined with HiC-seq analyses, we demonstrate that complex chromatin architecture changes including enhancer switching are coordinated with ER\u03b1 and PGR co-binding during diestrus and non-hormone receptor transcription factors such as HIF2A during estrus to regulate most differential gene expression across the estrous cycle.<\/jats:p>","DOI":"10.1093\/nar\/gkae714","type":"journal-article","created":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T22:18:21Z","timestamp":1724278701000},"page":"10897-10917","source":"Crossref","is-referenced-by-count":22,"title":["Unexpected nuclear hormone receptor and chromatin dynamics regulate estrous cycle dependent gene expression"],"prefix":"10.1093","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5741-2159","authenticated-orcid":false,"given":"Wendy\u00a0N","family":"Jefferson","sequence":"first","affiliation":[{"name":"Reproductive & Developmental Biology Laboratory , Research Triangle Park, NC 27709,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3970-0771","authenticated-orcid":false,"given":"Tianyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH , Research Triangle Park , NC\u00a0 27709 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Padilla-Banks","sequence":"additional","affiliation":[{"name":"Reproductive & Developmental Biology Laboratory , Research Triangle Park, NC 27709,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6440-7086","authenticated-orcid":false,"given":"Carmen\u00a0J","family":"Williams","sequence":"additional","affiliation":[{"name":"Reproductive & Developmental Biology Laboratory , Research Triangle Park, NC 27709,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,8,21]]},"reference":[{"key":"2024101409454821400_B1","doi-asserted-by":"crossref","first-page":"R127","DOI":"10.1530\/JME-15-0300","article-title":"Mechanisms of uterine estrogen signaling during early pregnancy in mice: an update","volume":"56","author":"Robertshaw","year":"2016","journal-title":"J. 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