UC San Diego

Follicle- stimulating hormone (FSH) is a glycoprotein hormone that is an essential regulator of mammalian fertility. Produced within gonadotrope cells in the anterior pituitary, FSH, along with the other pituitary gonadotropin, luteinizing hormone, act on the gonads to regulate pubertal maturation, hormone synthesis, and gametogenesis. Genome-wide association studies (GWAS) link a 130 Kb locus at 11p14.1 that encompasses the FSH beta-subunit gene (FSHB) with fertility-related traits including polycystic ovary syndrome, age of natural menopause, and dizygotic twinning. The rate-limiting step in FSH synthesis is transcription of the beta subunit. Therefore, understanding the transcriptional regulation of FSHB is critical to understand how FSHB dysregulation contributes to infertility. The lead single nucleotide polymorphism from several studies is rs11031006, which resides within a highly evolutionarily conserved, ~450 base pair element located 26 Kb upstream of the FSHB transcriptional start site in humans. We hypothesized that the highly conserved element is an enhancer of FSHB and that the minor allele of the rs11031006 polymorphism would impair FSHB transcription. Chapter 1 describes the conserved element in the context of basal regulation and demonstrates that it is, indeed, an enhancer of FSHB transcription in human and mouse. Counter to our initial hypothesis, the rs11031006 variant increased, rather than decreased, FSHB transcription, likely through creation of a higher affinity binding site for the transcription factor Steroidogenic factor 1. Chapter 2 describes the role of the novel FSHB enhancer in the context of hormone regulation. The enhancer potentiated activin- and gonadotropin-releasing hormone- induction of FSHB, dependent upon a binding site within the enhancer for SMAD transcription factors, which are downstream effectors of activin signaling. Chapter 3 examines the in vivo necessity of the Fshb enhancer in a mouse model and the effect of the rs11031006 minor allele. Neither deletion of the enhancer or the rs11031006 minor allele impaired adult fertility, possibly indicating that other enhancers of Fshb can compensate. Overall, we identified a novel enhancer of basal and hormone-stimulated FSHB transcription and demonstrate that the rs11031006 allele increases the activity of the enhancer, although the role of the enhancer and rs11031006 variant in vivo requires further resolution.