# Investigating the role of an FSHβ enhancer in FSHβ expression and polycystic ovary syndrome

> **NIH NIH F31** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2020 · $40,258

## Abstract

PROJECT SUMMARY
Polycystic ovary syndrome (PCOS) is a leading cause of female infertility and a tremendous health burden,
associated with complications such as cardiovascular disease and type 2 diabetes. The etiology of PCOS is
unknown, but twin studies suggest that over 70% of PCOS pathogenesis can be explained by genetics.
Genome-wide association studies (GWAS) aimed to identify the genetic components of PCOS uncovered two
single nucleotide polymorphisms (SNPs) in the 5’ upstream regulatory region of the gene encoding the follicle-
stimulating hormone (FSH) beta subunit in association with PCOS and gonadotropin levels. The
gonadotropins, FSH and luteinizing hormone (LH), represent the pituitary output of the HPG axis. Women with
PCOS often have an elevated LH to FSH ratio, indicating that deficient FSH secretion may play a causative
role in the development of PCOS. The two PCOS-related SNPs identified through GWAS (referred to here as
“rs05” and “rs06”) are contained within a short, evolutionarily conserved element, which is suggestive of an
important biological function. We hypothesize that the conserved element functions as an enhancer of FSHβ,
is required for female fertility, and that the SNPs alter FSHβ transcription. We will test this hypothesis through
two specific aims, which will address in vitro and in vivo (1) the role of the conserved element as a FSHβ
transcriptional enhancer, and (2) the effect of the SNPs on FSHβ transcription and the underlying molecular
mechanisms. Both aims are well-supported by our preliminary in vitro data, which reveal that the conserved
element from both the human and mouse genome functions as an enhancer of FSHβ and demonstrates an
effect of both SNPs on FSHβ transcription and transcription factor binding. The proposed experiments will
expand upon these data through both in vitro and in vivo experiments. In vitro, we will map enhancer and
repressor sites within the conserved element, assess chromatin status near the conserved element, and
identify transcription factor binding sites that are functionally altered by the SNPs. To elucidate how effects of
the conserved element and SNPs interact with hormones that regulate FSHβ transcription, we will perform all
in vitro experiments in basal conditions and with treatment of gonadotropin-releasing hormone, activin, and
testosterone. To determine how the conserved element and the SNPs affect female fertility in vivo, we will
develop two novel mouse models, one with a deletion of the conserved element and one with the rs06 SNP
minor allele (the rs05 SNP is not conserved between humans and mice). We will conduct a thorough fertility
analysis of both mouse lines, measuring ovulation, fecundity, and hormone levels. Through our specific aims,
this proposal will define novel factors that regulate FSHβ transcription and will help us to understand the
contributions of FSHβ in the pathophysiology of PCOS, which will lead to improved diagnosis and treatment.

## Key facts

- **NIH application ID:** 9995549
- **Project number:** 5F31HD096838-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Stephanie Bohaczuk
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,258
- **Award type:** 5
- **Project period:** 2018-07-06 → 2021-07-05

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9995549

## Citation

> US National Institutes of Health, RePORTER application 9995549, Investigating the role of an FSHβ enhancer in FSHβ expression and polycystic ovary syndrome (5F31HD096838-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9995549. Licensed CC0.

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