{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,4]],"date-time":"2025-10-04T07:40:04Z","timestamp":1759563604217,"version":"3.37.3"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18\u00a0K07839"],"award-info":[{"award-number":["18\u00a0K07839"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The genetic regulation of ovarian development remains largely unclear. Indeed, in most cases of impaired ovarian development\u2014such as 46,XX disorders of sex development (DSD) without SRY, and premature ovarian insufficiency (POI)\u2014the genetic causes have not been identified, and the vast majority of disease-associated sequence variants could lie within non-coding regulatory sequences. In this study, we aimed to identify enhancers of five ovarian genes known to play key roles in early ovarian development, basing our analysis on the expression of enhancer derived transcripts (eRNAs), which are considered to characterize active enhancers. Temporal expression profile changes in mouse WT1-positive ovarian cells were obtained from cap analysis of gene expression at E13.5, E16.5 and P0. We compared the chronological expression profiles of ovarian-specific eRNA with expression profiles for each of the ovarian-specific genes, yielding two candidate sequences for enhancers of Wnt4 and Rspo1. Both sequences are conserved between mouse and human, and we confirmed their enhancer activities using transient expression assays in murine granulosa cells. Furthermore, by sequencing the region in patients with impaired ovarian development in 24 patients, such as POI, gonadal dysgenesis and 46,XX DSD, we identified rare single nucleotide variants in both sequences. Our results demonstrate that combined analysis of the temporal expression profiles of eRNA and mRNA of target genes presents a powerful tool for locating cis-element enhancers, and a means of identifying disease-associated sequence variants that lie within non-coding regulatory sequences, thus advancing an important unmet need in forward human genetics.<\/jats:p>","DOI":"10.1093\/hmg\/ddac023","type":"journal-article","created":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T12:12:04Z","timestamp":1643890324000},"page":"2223-2235","source":"Crossref","is-referenced-by-count":4,"title":["Two ovarian candidate enhancers, identified by time series enhancer RNA analyses, harbor rare genetic variations identified in ovarian insufficiency"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4166-3279","authenticated-orcid":false,"given":"Ryuichi","family":"Nakagawa","sequence":"first","affiliation":[{"name":"Department of Pediatrics and Developmental Biology , Tokyo Medical and Dental University (TMDU), Tokyo 113-8510 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kei","family":"Takasawa","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Developmental Biology , Tokyo Medical and Dental University (TMDU), Tokyo 113-8510 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maki","family":"Gau","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Developmental Biology , Tokyo Medical and Dental University (TMDU), Tokyo 113-8510 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8226-2618","authenticated-orcid":false,"given":"Atsumi","family":"Tsuji-Hosokawa","sequence":"additional","affiliation":[{"name":"Department of Systems BioMedicine , National Research Institute for Child Health and Development, Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideya","family":"Kawaji","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 , Japan"},{"name":"Research Center for Genome & Medical Sciences , Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuhiro","family":"Murakawa","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Kanagawa 230-0045 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9406-4683","authenticated-orcid":false,"given":"Shuji","family":"Takada","sequence":"additional","affiliation":[{"name":"Department of Systems BioMedicine , National Research Institute for Child Health and Development, Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masashi","family":"Mikami","sequence":"additional","affiliation":[{"name":"Division of Biostatistics , Clinical Research Center, National Center for Child Health and Development, Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Satoshi","family":"Narumi","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology , National Research Institute for Child Health and Development, Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maki","family":"Fukami","sequence":"additional","affiliation":[{"name":"Department of Molecular Endocrinology , National Research Institute for Child Health and Development, Tokyo 157-8535 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rajini","family":"Sreenivasan","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute and Department of Paediatrics , University of Melbourne, Melbourne, VIC 3052 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tetsuo","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology , Keio University School of Medicine, Tokyo 160-8582 , Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena J","family":"Tucker","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute and Department of Paediatrics , University of Melbourne, Melbourne, VIC 3052 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience , The University of Queensland, Brisbane, QLD 4072 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Josephine","family":"Bowles","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience , The University of Queensland, Brisbane, QLD 4072 , Australia"},{"name":"School of Biomedical Sciences , The University of Queensland, Brisbane, QLD 4072 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Sinclair","sequence":"additional","affiliation":[{"name":"Murdoch Children's Research Institute and Department of Paediatrics , University of Melbourne, Melbourne, VIC 3052 Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6939-0914","authenticated-orcid":false,"given":"Peter","family":"Koopman","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience , The University of Queensland, Brisbane, QLD 4072 , Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihide","family":"Hayashizaki","sequence":"additional","affiliation":[{"name":"RIKEN Preventive Medicine and Diagnosis Innovation Program , Saitama 351-0198 , 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