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FSHB Transcription is Regulated by a Novel 5′ Distal Enhancer With a Fertility-Associated Single Nucleotide Polymorphism
- Source :
- Endocrinology
- Publication Year :
- 2020
- Publisher :
- The Endocrine Society, 2020.
-
Abstract
- The pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone, signal the gonads to regulate male and female fertility. 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 LβT2 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.
- Subjects :
- 0301 basic medicine
Steroidogenic factor 1
endocrine system
medicine.medical_specialty
Biology
Gonadotropic cell
Polymorphism, Single Nucleotide
FSHB
Histones
Mice
03 medical and health sciences
0302 clinical medicine
Endocrinology
Transcription (biology)
Internal medicine
medicine
Animals
Humans
Genetic Predisposition to Disease
Enhancer
Research Articles
030219 obstetrics & reproductive medicine
Polycystic ovary
Chromatin
Cell biology
030104 developmental biology
Gene Expression Regulation
Follicle Stimulating Hormone, beta Subunit
NIH 3T3 Cells
Female
Luteinizing hormone
Infertility, Female
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 19457170 and 00137227
- Volume :
- 162
- Database :
- OpenAIRE
- Journal :
- Endocrinology
- Accession number :
- edsair.doi.dedup.....40714d10ea43aa5c3156457a6d85957f