Regulation of murine follicle-stimulating hormone β subunit transcription by newly identified enhancers
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE310461 | GEO | 2025/11/24
REPOSITORIES: GEO
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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
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
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. 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.
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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
Project description:The pituitary regulates growth, reproduction and other endocrine systems. To investigate transcriptional network epigenetic mechanisms in this gland, we generated paired single nucleus (sn) transcriptome and chromatin accessibility profiles in single mouse pituitaries, and genome-wide sn methylation datasets. Our analysis provided insight into cell type epigenetics, regulatory circuit and gene control mechanisms. Latent variable transcriptome and accessibility data representation resolved both inter-sexual and inter-individual variation in gene control programs. Multi-omics analysis of cell type-specific gene regulatory networks distinguished distinct mechanisms. Particularly, the FoxL2 gonadotrope network is controlled both by FoxL2 expression and by target gene epigenetic status. Co-accessibility analysis comprehensively identified putative regulatory regions, including a region that overlapped the fertility-linked rs11031006 human polymorphism. In vitro CRISPR-deletion at this locus increased Fshb levels, supporting this domain’s predicted regulatory role. The public pituitary atlas [link] is a resource for elucidating cell-type specific gene regulatory mechanisms and principles of transcription circuit control.
2021-02-23 | GSE151960 | GEO
Project description:The pituitary regulates growth, reproduction and other endocrine systems. To investigate transcriptional network epigenetic mechanisms in this gland, we generated paired single nucleus (sn) transcriptome and chromatin accessibility profiles in single mouse pituitaries, and genome-wide sn methylation datasets. Our analysis provided insight into cell type epigenetics, regulatory circuit and gene control mechanisms. Latent variable transcriptome and accessibility data representation resolved both inter-sexual and inter-individual variation in gene control programs. Multi-omics analysis of cell type-specific gene regulatory networks distinguished distinct mechanisms. Particularly, the FoxL2 gonadotrope network is controlled both by FoxL2 expression and by target gene epigenetic status. Co-accessibility analysis comprehensively identified putative regulatory regions, including a region that overlapped the fertility-linked rs11031006 human polymorphism. In vitro CRISPR-deletion at this locus increased Fshb levels, supporting this domain’s predicted regulatory role. The public pituitary atlas [link] is a resource for elucidating cell-type specific gene regulatory mechanisms and principles of transcription circuit control.
2021-02-23 | GSE151961 | GEO
Project description:The pituitary regulates growth, reproduction and other endocrine systems. To investigate transcriptional network epigenetic mechanisms in this gland, we generated paired single nucleus (sn) transcriptome and chromatin accessibility profiles in single mouse pituitaries, and genome-wide sn methylation datasets. Our analysis provided insight into cell type epigenetics, regulatory circuit and gene control mechanisms. Latent variable transcriptome and accessibility data representation resolved both inter-sexual and inter-individual variation in gene control programs. Multi-omics analysis of cell type-specific gene regulatory networks distinguished distinct mechanisms. Particularly, the FoxL2 gonadotrope network is controlled both by FoxL2 expression and by target gene epigenetic status. Co-accessibility analysis comprehensively identified putative regulatory regions, including a region that overlapped the fertility-linked rs11031006 human polymorphism. In vitro CRISPR-deletion at this locus increased Fshb levels, supporting this domain’s predicted regulatory role. The public pituitary atlas [link] is a resource for elucidating cell-type specific gene regulatory mechanisms and principles of transcription circuit control.
2021-02-23 | GSE151958 | GEO
Project description:Gonadotropin-releasing hormone (GnRH) is secreted in brief pulses from the hypothalamus. GnRH regulates follicle-stimulating hormone b-subunit (FSHb) gene expression in pituitary gonadotropes in a frequency-sensitive manner that is central to reproductive physiology. The mechanisms underlying the preferential and paradoxical induction of FSHb by low frequency GnRH pulses are incompletely understood. Here, we identify growth differentiation factor 9 (GDF9) as a novel autocrine inducer of FSHb gene expression. GDF9 gene expression was preferentially suppressed by high frequency GnRH pulses due to reduced transcription. Exogenous GDF9 induced FSHb mRNA expression and knockdown or immunoneutralization of GDF9 reduced FSHb gene expression. Treatment with GDF9 stimulated Smad2/3 phosphorylation. The activin receptor-like kinase (ALK) receptor inhibitor SB-505124 antagonized GDF9-induced Smad2/3 phosphorylation and FSHb mRNA induction. Smad2 and Smad3 knockdown studies indicated that the induction of FSHb by GDF9 involves both Smad2 and Smad3. GDF9 and GnRH synergistically induced FSHb mRNA expression and high frequency GnRH pulses suppressed GDF9. We hypothesized that GDF9 contributes to a regulatory loop that tunes the GnRH frequency-response characteristics of the FSHb gene. To test this, we determined the effects of GDF9 knockdown on FSHb induction at different GnRH pulse frequencies using a parallel perifusion system. Reduction of GDF9 shifted the characteristic pattern of GnRH pulse frequency sensitivity. These results identify GDF9 as contributing to an incoherent feed-forward loop, comprised of both intracellular and secreted elementscomponents, that regulates FSHb expression in response to activation of the cell surface GnRH receptor. LbT2 microarray datasets as well as RNA-Seq data (GSE42120) were interrogated to determine the levels of expression of ALK4/5/7. LM-NM-2T2 cells were transfected with either scrambled siRNA or Gas siRNA for 48 h. RNA samples were snap-frozen in dry ice prior to whole-genome expression profiling analysis using MouseWG-6 v2.0 Expression BeadChip (Illumina, San Diego, CA). A total of 6 concentrated conditioned media samples were independently prepared: 3 replicates from control siRNA-treated cells, and 3 replicates from Gas siRNA-treated cells. This submission represents the microarray component of study.
2013-11-22 | E-GEOD-52631 | biostudies-arrayexpress
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
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 | GSE189915 | GEO