10.6075/J09885DG
Bohaczuk, Stephanie C.
0000-0001-8802-6579
University of California, San Diego
Thackray, Varykina G.
University of California, San Diego
Shen, Jia
University of California, San Diego
Skowronska-Krawczyk, Dorota
University of California, San Diego
Mellon, Pamela L.
0000-0002-8856-0410
University of California, San Diego
Data from: FSHB transcription is regulated by a novel 5’ distal enhancer
containing a fertility-associated single nucleotide polymorphism
Dryad
dataset
2020
FOS: Biological sciences
Fshb
Polycystic ovary syndrome (PCOS)
rs11031006
single nucleotide polymorphism (SNP)
NR5A1
scATAC-seq
Eunice Kennedy Shriver National Institute of Child Health and Human Development
https://ror.org/04byxyr05
R01 HD082567
Eunice Kennedy Shriver National Institute of Child Health and Human Development
https://ror.org/04byxyr05
R01 HD072754
Eunice Kennedy Shriver National Institute of Child Health and Human Development
https://ror.org/04byxyr05
R01 HD100580
Eunice Kennedy Shriver National Institute of Child Health and Human Development
https://ror.org/04byxyr05
P50 HD012303
National Institute of Diabetes and Digestive and Kidney Diseases
https://ror.org/00adh9b73
P30 DK063491
National Cancer Institute
https://ror.org/040gcmg81
P30 CA023100
National Institute of Environmental Health Sciences
https://ror.org/00j4k1h63
P42 ES010337
Eunice Kennedy Shriver National Institute of Child Health and Human Development
https://ror.org/04byxyr05
F31 HD096838
National Institute of Neurological Disorders and Stroke
https://ror.org/01s5ya894
T32 NS061847
Eunice Kennedy Shriver National Institute of Child Health and Human Development
https://ror.org/04byxyr05
R01 HD095412
National Eye Institute
https://ror.org/03wkg3b53
R01 EY027011
Research to Prevent Blindness
https://ror.org/04drjs621
Special Scholar Award
2020-10-07T00:00:00Z
2020-10-07T00:00:00Z
en
https://doi.org/10.1210/endocr/bqaa181
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE158070
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CC0 1.0 Universal (CC0 1.0) Public Domain Dedication
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.
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).