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FSH is critical for female fertility as it regulates oocyte maturation, ovulation, and hormone synthesis. Multiple genome-wide association studies (GWAS) link a 130 Kb locus at 11p14.1, which encompasses the FSH beta-subunit (FSHB) gene, with fertility-related traits that include polycystic ovary syndrome, age of natural menopause, and dizygotic twinning. The most statistically significant single nucleotide polymorphism from several GWAS studies (rs11031006) resides within a highly conserved 450 bp region 26 Kb upstream of the human FSHB gene. Given that sequence conservation suggests an important biological function, we hypothesized that the region could regulate FSHB transcription. In luciferase assays, the conserved region enhanced FSHB transcription and gel shifts identified a binding site for Steroidogenic factor 1 (SF1) contributing to its function. Analysis of mouse pituitary single-cell ATAC-seq demonstrated open chromatin at the conserved region exclusive to a gonadotrope cell-type cluster. Additionally, enhancer-associated histone markers were identified by immunoprecipitation of chromatin from mouse whole pituitary and an immortalized mouse gonadotrope-derived L\u03b2T2 cell line at the conserved region. Furthermore, we found that the rs11031006 minor allele upregulated FSHB transcription via increased SF1 binding to the enhancer. All together, these results identify a novel upstream regulator of FSHB transcription and indicate that rs11031006 can modulate FSH levels.<\/jats:p>","DOI":"10.1210\/endocr\/bqaa181","type":"journal-article","created":{"date-parts":[[2020,10,3]],"date-time":"2020-10-03T03:33:49Z","timestamp":1601696029000},"source":"Crossref","is-referenced-by-count":35,"title":["<i>FSHB<\/i>\n                    \u2009Transcription is Regulated by a Novel 5\u2032 Distal Enhancer With a Fertility-Associated Single Nucleotide Polymorphism"],"prefix":"10.1210","volume":"162","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-6579","authenticated-orcid":false,"given":"Stephanie C","family":"Bohaczuk","sequence":"first","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6672-6117","authenticated-orcid":false,"given":"Varykina G","family":"Thackray","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7139-9889","authenticated-orcid":false,"given":"Jia","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Medicine, School of Medicine, University of California San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5758-4225","authenticated-orcid":false,"given":"Dorota","family":"Skowronska-Krawczyk","sequence":"additional","affiliation":[{"name":"Shiley Eye Institute, Viterbi Family Department of Ophthalmology, School of Medicine, University of California, San Diego, California"},{"name":"Department of Physiology and Biophysics, Department of Ophthalmology, Center for Translational Vision Research, School of Medicine, University of California Irvine, Irvine, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8856-0410","authenticated-orcid":false,"given":"Pamela L","family":"Mellon","sequence":"additional","affiliation":[{"name":"Department of Obstetrics, Gynecology, and Reproductive Sciences, Center for Reproductive Science and Medicine, University of California San Diego, La Jolla, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2020,10,3]]},"reference":[{"issue":"1","key":"2021121701461023000_CIT0001","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1093\/nar\/30.1.113","article-title":"The Mouse Genome Database (MGD): the model organism 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