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We aimed here to identify factors responsible for repressing Mkrn3 expression across the pubertal transition, initially through bioinformatic analysis of developmental RNA-seq datasets from rodent tissues. Genes whose expression correlated significantly with Mkrn3, and are linked to puberty and signaling, were identified. Notably, these included Acvr1c, whose knockout was shown previously to delay puberty in mice. Experimentally, we show that Acvr1c activation suppresses Mkrn3 via Smad2\/3 signaling, involving recruitment of Kap1 and repressive histone modifications. These findings provide mechanistic explanation for the reduction in Mkrn3 required for pubertal onset, while underscoring the value of integrating high-throughput gene expression analyses with experimental validation to uncover novel regulatory pathways.<\/jats:p>","DOI":"10.1093\/narmme\/ugaf008","type":"journal-article","created":{"date-parts":[[2025,3,29]],"date-time":"2025-03-29T18:57:46Z","timestamp":1743274666000},"source":"Crossref","is-referenced-by-count":2,"title":["High-throughput transcriptome analysis reveals a developmental increase in Acvr1c which mediates epigenetic repression of the gene encoding the pubertal brake, Makorin ring finger protein 3"],"prefix":"10.1093","volume":"2","author":[{"given":"Dor","family":"Shalev","sequence":"first","affiliation":[{"name":"Faculty of Biology, Technion-Israel Institute of Technology , Haifa 3200003,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gil","family":"Golan","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Technion-Israel Institute of Technology , Haifa 3200003,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilach","family":"Pnueli","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Technion-Israel Institute of Technology , Haifa 3200003,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anat","family":"Kahan","sequence":"additional","affiliation":[{"name":"Faculty of Agriculture, Hebrew University of Jerusalem , Rehovot 7610001,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Mandel-Gutfreund","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Technion-Israel Institute of Technology , Haifa 3200003,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7814-6542","authenticated-orcid":false,"given":"Philippa","family":"Melamed","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Technion-Israel Institute of Technology , Haifa 3200003,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,3,25]]},"reference":[{"key":"2025033000432678300_B1","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1210\/endrev\/bnac020","article-title":"The congenital and acquired mechanisms implicated in the etiology of Central precocious puberty","volume":"44","author":"Brito","year":"2023","journal-title":"Mol Cell"},{"key":"2025033000432678300_B2","doi-asserted-by":"publisher","first-page":"2838","DOI":"10.1093\/humrep\/deu256","article-title":"A novel MKRN3 missense mutation causing familial precocious puberty","volume":"29","author":"De","year":"2014","journal-title":"Hum Reprod"},{"key":"2025033000432678300_B3","doi-asserted-by":"publisher","first-page":"2467","DOI":"10.1056\/NEJMoa1302160","article-title":"Central precocious puberty caused by mutations in the imprinted gene MKRN3","volume":"368","author":"Abreu","year":"2013","journal-title":"N Engl J. 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