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Regulation of murine follicle-stimulating hormone β subunit transcription by newly identified enhancers [scATAC-seq; Mouse Pituitaries]

ABSTRACT: Activin-class ligands of the TGFβ family induce follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells in mice via the actions of the transcription factors SMAD3, SMAD4, and FOXL2, which bind to cis-elements in the FSHβ subunit (Fshb) promoter. An enhancer region for murine Fshb transcription was identified in vitro. However, deletion of the region using CRISPR-Cas9 did not affect FSH synthesis or secretion in mice. Using single-nucleus ATAC-seq of whole pituitaries, we identified three additional chromatin regions upstream of Fshb open exclusively in murine gonadotropes. We found these regions, as well as the Fshb gene, to be fully or partially closed in gonadotropes of FSH-deficient mice with genetically or pharmacologically inactivated activin type II receptors. The data indicate that there may be as many as four activin-sensitive enhancers upstream of murine Fshb. This data is part of a SuperSeries that includes bulk ATAC-seq and ChIP-seq data of gonadotrope-derived LβT2 cells, that substantiate the above conclusions.

ORGANISM(S): Mus musculus

PROVIDER: GSE310460 | GEO | 2025/11/24

REPOSITORIES: GEO

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Similar Datasets

Regulation of murine follicle-stimulating hormone β subunit transcription by newly identified enhancers [ATAC-seq; LβT2 cells]

Project description:Activin-class ligands of the TGFβ family induce follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells in mice via the actions of the transcription factors SMAD3, SMAD4, and FOXL2, which bind to cis-elements in the FSHβ subunit (Fshb) promoter. An enhancer region for murine Fshb transcription was identified in vitro. The region, however, did not significantly alter basal or activin-stimulated murine Fshb promoter-reporter activity in LβT2 cells. In contrast, three other open chromatin regions enhanced basal and activin A-stimulated Fshb promoter-reporter activity in LβT2 cells, with the two most distal showing the greatest effects. Using ATAC-seq we show that these two regions were open in response to activin A in LβT2 cells. This data is part of a SuperSeries that includes ChIP-seq data further showing that these regions exhibited enrichment of the enhancer mark H3K27ac, and were bound by SMAD2/3 and FOXL2 in response to activin A in LβT2 cells. The SuperSeries also includes scATAC-seq data of whole mouse pituitaries indicating that there may be as many as four activin-sensitive enhancers upstream of murine Fshb.

2025-11-24 | GSE310458 | GEO

Regulation of murine follicle-stimulating hormone β subunit transcription by newly identified enhancers

Project description:Activin-class ligands of the TGFβ family stimulate follicle-stimulating hormone (FSH) synthesis in pituitary gonadotrope cells through SMAD3/SMAD4 and FOXL2-mediated transcriptional regulation of Fshb. This SuperSeries integrates chromatin accessibility and transcription factor binding datasets to identify activin-sensitive regulatory regions controlling Fshb expression. It includes single-nucleus ATAC-seq of mouse pituitaries, and bulk ATAC-seq and ChIP-seq of gonadotrope-derived LβT2 cells. Together, these datasets indicate that there may be as many as four activin-sensitive enhancers upstream of murine Fshb.

2025-11-24 | GSE310461 | GEO

Regulation of murine follicle-stimulating hormone β subunit transcription by newly identified enhancers [ChIP-seq; LβT2 cells]

Project description:Activin-class ligands of the TGFβ family induce follicle-stimulating hormone (FSH) production by pituitary gonadotrope cells in mice via the actions of the transcription factors SMAD3, SMAD4, and FOXL2, which bind to cis-elements in the FSHβ subunit (Fshb) promoter. An enhancer region for murine Fshb transcription was identified in vitro. The region, however, did not significantly alter basal or activin-stimulated murine Fshb promoter-reporter activity in LβT2 cells. In contrast, three other open chromatin regions enhanced basal and activin A-stimulated Fshb promoter-reporter activity in LβT2 cells, with the two most distal showing the greatest effects. Using ChIP-seq we show that these two regions exhibit enrichment of the enhancer mark H3K27ac, and are bound by SMAD2/3 and FOXL2 in response to activin A in LβT2 cells. This data is part of a SuperSeries that includes ATAC-seq data also showing these regions to be open in response to activin A in LβΤ2 cells, as well as scATAC-seq data of whole mouse pituitaries indicating that there may be as many as four activin-sensitive enhancers upstream of murine Fshb.

2025-11-24 | GSE310459 | GEO

FSH-deficiency in gonadotrope-specific GATA2 knockout mice is associated with a loss of gremlin expression [snATAC-Seq]

Project description:Mammalian reproduction is dependent on the gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone, which are secreted by pituitary gonadotrope cells. The zinc-finger transcription factor, GATA2, was previously implicated in FSH production in male mice, although its mechanisms of action and role in females were not determined. To address these gaps in knowledge, we generated and analyzed gonadotrope-specific Gata2 knockout mice using the Cre-lox system. While conditional knockout (cKO) males exhibited ~50% reductions in serum FSH levels and pituitary FSHβ subunit (Fshb) expression relative to controls, FSH production was apparently normal in cKO females. RNA-seq analysis of purified gonadotropes from control and cKO males revealed a profound decrease in expression of gremlin (Grem1), a bone morphogenetic protein (BMP) antagonist. Grem1 was expressed in gonadotropes, but not other cell lineages, in the adult male mouse pituitary. Gata2, Grem1, and Fshb mRNA levels were significantly higher in pituitaries of wild-type males relative to females but decreased in males treated with estradiol and increased following ovariectomy in control but not cKO females. Recombinant gremlin stimulated Fshb expression in pituitary cultures from wild-type mice. Collectively, the data suggest that GATA2 promotes Grem1 expression in gonadotropes and that the gremlin protein potentiates FSH production. The mechanisms of gremlin action have not yet been established but may involve attenuation of BMP binding to activin type II receptors in gonadotropes, potentiating induction of Fshb transcription by activins or related ligands.

2022-07-14 | GSE190064 | GEO

FSH-deficiency in gonadotrope-specific GATA2 knockout mice is associated with a loss of gremline expression

2022-07-14 | GSE189915 | GEO

FSH-deficiency in gonadotrope-specific GATA2 knockout mice is associated with a loss of gremlin expression [snRNA-Seq]

2022-07-14 | GSE190060 | GEO

Activating-transcription factor 3 stimulates follicle-stimulating hormone β transcription in vitro, but is dispensable for FSH production in murine gonadotropes in vivo

Project description:Follicle-stimulating hormone (FSH), a dimeric glycoprotein produced by pituitary gonadotrope cells, regulates spermatogenesis in males and ovarian follicle growth in females. Hypothalamic gonadotropin-releasing hormone (GnRH) stimulates FSHβ subunit gene (Fshb) transcription, though the underlying mechanisms are poorly understood. To address this gap in knowledge, we examined changes in pituitary gene expression in GnRH-deficient mice (hpg) treated with a regimen of exogenous GnRH that increases pituitary Fshb but not luteinizing hormone β (Lhb) mRNA levels. Activating transcription factor 3 (Atf3) was among the most upregulated genes. ATF3 can heterodimerize with members of the AP-1 family to regulate gene transcription. Co-expression of ATF3 with JunB stimulated murine Fshb, but not Lhb, promoter-reporter activity in homologous LβT2 cells. ATF3 also synergized with a constitutively active activin type I receptor to increase endogenous Fshb expression in these cells. Nevertheless, FSH production was intact in gonadotrope-specific Atf3 knockout mice (cKO) and control littermates. Ovarian follicle development, ovulation, and litter sizes were also equivalent between genotypes. Testis weights and sperm counts did not differ between cKO and control males. Following gonadectomy, increases in LH secretion were enhanced in cKO animals. Though FSH levels did not differ between genotypes, post-gonadectomy increases in pituitary Fshb and gonadotropin α subunit expression were more pronounced in cKO mice. These data indicate that ATF3 can selectively stimulate Fshb transcription in vitro but is not required for FSH production in vivo.

2023-06-28 | GSE220809 | GEO

Gonadotropin-releasing hormone 3 and gonadotropes relationships in female zebrafish pituitary revealed by single-cell transcriptomics

Project description:Gonadotropin-releasing hormone (GnRH) governs reproduction in vertebrates by regulating pituitary gonadotropins. Zebrafish, however, is an exception as gnrh3–/– fish, which lack the hypophysiotropic GnRH3, are fertile, suggesting that zebrafish utilizes a Gnrh-independent mechanism to regulate reproduction. To elucidate the role of Gnrh3 and the Gnrh-independent mechanisms that regulate the pituitary gonadotropes, we profiled the gene expression in individual pituitary cells of wild-type and gnrh–/– adult female zebrafish and identified transcriptionally defined cell types. The classical Lh and Fsh gonadotropes expressed both gonadotropin beta subunits with a ratio of 13:1 (lhb:fshb) and 40:1 (fshb:lhb), respectively. We discovered that Lh gonadotropes predominantly express genes encoding receptors for Gnrh (gnrhr2), thyroid hormone, estrogen, dopamine, and steroidogenic factor 1 (SF1). No Gnrh receptor expression was enriched in Fsh gonadotropes, instead, the expression of cholecystokinin receptor (cckrb) and galanin receptor (gal1rb) were enriched in these cells. The hereditary loss of Gnrh3 gene resulted in downregulation of fshb in Lh gonadotropes. Likewise, targeted chemogenetic ablation of Gnrh3 neurons led to a decrease in the number of fshb+/lhb+ cells. Our studies suggest that Gnrh3 directly acts on Lh gonadotropes through Gnrhr2, but the outcome of this interaction is still unknown. Gnrh3 also regulates fshb expression, probably via a non-Gnrh receptor route. Altogether, while Lh secretion and synthesis are likely regulated by multiple factors in a Gnrh-independent manner, Gnrh3 seems to play a role in the cellular organization of the pituitary in zebrafish.

2024-11-20 | GSE272806 | GEO

Identification of FSH-regulated and estrous stage-specific transcriptional networks in mouse ovaries

Project description:Follicle-stimulating hormone (FSH) acts by binding to FSHRs on ovarian granulosa cells to produce estradiol. FSH is essential for female fertility because mice lacking FSH (Fshb KO) are anestrus, and infertile. Although several in vitro and ex vivo cell culture approaches combined with pharmacological hormone treatments were used to identify FSH-regulated genes, how FSH orchestrates ovarian gene networks in vivo has not been investigated. Similarly, whether FSH-regulated genes display estrus stage-specific expression changes has also not been studied. Here, we functionally rescued Fshb null mice with a well-established gonadotrope-targeted HFSHB transgene-mediated in vivo genetic rescue approach and performed RNA-Seq analysis on ovarian RNAs obtained from FSH-intact (WT), FSH-deficient (Fshb KO) and FSH-rescue (HFSHB+ rescue) mice. By comparing WT vs Fshb KO and Fshb KO vs Fshb KO HFSHB+ ovarian gene expression datasets, we identified bona-fide FSH-responsive genes in vivo in mouse ovaries. Cross interrogation of WT vs Fshb KO and Fshb KO vs Fshb KO HFSHB+ data sets further allowed us to identify several transcription factors and RNA-binding proteins specifically in FSH - regulated genes. In an independent set of experiments, we performed RNA-Seq analysis on ovarian RNAs obtained from mice in diestrus (DE), proestrus (PE) and estrus (E) stages and identified estrus stage-specific ovarian gene expression patterns. Interestingly, many of the FSH-regulated transcription factors themselves were estrus-stage specifically expressed. We found that ESR2 and GATA6, two known FSH-responsive granulosa cell-specific transcription factors and their target genes are reciprocally regulated with distinct patterns of expression in estrus stages. Thus, our in vivo genetic models and RNA-Seq analyses identify FSH-regulated ovarian genes in specific estrus stages that are under transcriptional and post-transcriptional control.

2025-01-22 | GSE268258 | GEO

Foxo1/3 depletion in granulosa cells reveals novel mechanisms controlling follicle growth and death and endocrine regulation of pituitary FSH.

Project description:The Foxo transcription factors regulate multiple cellular functions. Foxo1 and Foxo3 are highly expressed in granulosa cells of ovarian follicles. Selective depletion of the Foxo1 and Foxo3 genes in granulosa cells revealed a novel ovarian-pituitary endocrine feedback loop characterized by: 1) undetectable levels of serum FSH but not LH, 2) reduced expression of the pituitary Fshb gene and its transcriptional regulators and 3) ovarian production of a factor(s) that suppresses pituitary cell Fshb. Equally notable and independent of FSH, depletion of Foxo1/3 altered the expression of specific genes associated with follicle growth versus apoptosis by disrupting critical regulatory interactions of Foxo1/3 with the activin and BMP2 pathways, respectively. As a consequence, granulosa cell proliferation and apoptosis were decreased. These data provide the first evidence that Foxo1/3 divergently regulate follicle growth or death by interacting with the activin and BMP pathways in granulosa cells and by modulating pituitary FSH production. A direct comparison of ovarian granulosa cells from wild type d25, Foxo1/3 dKO d25 and Foxo1/3 dKO 2 month mice.

2013-02-16 | E-GEOD-35593 | biostudies-arrayexpress

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