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Data from: FSHB transcription is regulated by a novel 5’ distal enhancer containing a fertility-associated single nucleotide polymorphism

Citation

Bohaczuk, Stephanie C. et al. (2020), Data from: FSHB transcription is regulated by a novel 5’ distal enhancer containing a fertility-associated single nucleotide polymorphism, Dryad, Dataset, https://doi.org/10.6075/J09885DG

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 including 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.

Usage Notes

Supplementary Figure S1: Chromatin accessibility from scATAC-seq with individual pituitary cell populations shown separately (grouped as “Other” in Fig. 2).

Supplementary Figure S2: scATAC-seq from a second pituitary, replication of Figure 2. scATAC-seq was used on adult male pituitary to evaluate chromatin accessibility to transposase digestion. (A) t-SNE analysis identified a cluster of gonadotopes (purple) marked by (B) chromatin accessibility at Lhb, Gnrhr, and (C) Fshb. Fshb enhancer chromatin was open in gonadotropes (boxed in blue) but not other pituitary cell-types (“other”, depicted in gray).

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Award: R01 HD082567

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Award: R01 HD072754

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Award: R01 HD100580

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Award: P50 HD012303

National Institute of Diabetes and Digestive and Kidney Diseases, Award: P30 DK063491

National Cancer Institute, Award: P30 CA023100

National Institute of Environmental Health Sciences, Award: P42 ES010337

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Award: F31 HD096838

National Institute of Neurological Disorders and Stroke, Award: T32 NS061847

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Award: R01 HD095412

National Eye Institute, Award: R01 EY027011

Research to Prevent Blindness, Award: Special Scholar Award