Single nucleus multi-omics regulatory atlas of the murine pituitary [single nuclei ATAC-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE151960 | GEO | 2021/02/23
REPOSITORIES: GEO
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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.
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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.
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Project description:The pituitary regulates growth, reproduction and other endocrine systems. To investigate transcriptional network epigenetic mechanisms, 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 pathway analysis detected corresponding transcriptome and chromatin accessibility programs showing both inter-sexual and inter-individual variation. Multi-omics analysis of gene regulatory networks identified regulons whose composition and function within specific cell types were shaped by the promoter accessibility state of target genes. Co-accessibility analysis comprehensively identified putative cis-regulatory regions, including a domain upstream of Fshb that overlapped the fertility-linked rs11031006 human polymorphism; In vitro CRISPR-deletion at this locus increased Fshb levels, supporting this domain’s inferred regulatory role. The sn pituitary multi-omics atlas [link] is a public resource for elucidating cell-type specific gene regulatory mechanisms and principles of transcription circuit control. This GEO series contain raw (FASTQ) and processed data (ALLC) files for the sn methylation dataset generated by the snmC-seq2 method.
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Project description:Foxl2 is a forkhead transcription factor essential for proper reproductive function in females. It is expressed in the somatic cell population of the gonad (granulosa cells) which forms the follicles of the ovary, the structures responsible for embedding and nurturing the oocytes during their development. FOXL2 directly regulate the aromatase that synthesizes estrogens CYP19A1, thus promoting female differentiation, as well as acting as a repressor of the male factors SOX9 and DMRT1.Expression is also found in the eyelids, pituitary gland and uterus. In the goat, frog and many fish species FOXL2 is a sex-determining gene which, when deleted, leads to female-to-male sex reversal.
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Project description:FOXL2 is a transcription factor essential for female fertility, expressed in somatic cells of the ovary, notably granulosa cells. In the mouse, Foxl2 deletion leads to partial sex reversal postnatally. However, deletion of the gene in 8-week-old females leads to granulosa to Sertoli cell transdifferentiation. We hypothesised that different outcomes of Foxl2 deletion in embryonic versus adult ovary may depend on a different role played across ovarian development. Therefore, we characterised the dynamics of gene expression and chromatin accessibility changes in purified murine granulosa cells across key developmental stages (E14.5, 1 and 8 weeks). We then performed genome-wide identification of FOXL2 target genes and on-chromatin interacting partners by ChIP-SICAP. We found that FOXL2 regulates more genes at postnatal stages, through the interaction with factors regulating primordial follicle activation (PFA), such as NR5A2, and others regulating steroidogenesis including AR and ESR2. As a proof of principle experiment, we chose one FOXL2 interactor, Ubiquitin specific protease 7 (USP7) and showed that deletion of this gene in granulosa cells leads to a blockage of PFA, impaired ovary development and sterility. Our study constitutes a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.
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Project description:Forkhead box L2 (FOXL2) is a single-exon gene encoding a forkhead transcription factor, which is mainly expressed in the ovary, eyelids and pituitary gland. FOXL2 plays an essential role in ovarian development. To reveal the effects of FOXL2 on biological process and gene expression of ovarian granulosa cells (GCs), we established stable FOXL2-knockdown GCs and then analyzed using transcriptome sequencing. It is observed that knockdown the FOXL2 affects the biological processes of cell proliferation, DNA replication, apoptosis and cell cycle. In which, the FOXL2 knockdown promoted cell proliferation and DNA replication, decreased cell apoptosis, and promoted mitosis. In addition, by comparing the transcriptome by FOXL2 knockdown, we found a serious of DEGs and their related pathways. These results indicated that, through mediating these genes and pathways, the FOXL2 might induce the cell proliferation, cycle, and DNA replication, and play a key role during ovarian development and maintenance.
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Project description:The transcription factor FOXL2 is required in ovarian somatic cells for female fertility. Differential timing of Foxl2 deletion, in embryonic versus adult mouse ovary, leads to distinctive outcomes, suggesting different roles across development. Here, we comprehensively investigated FOXL2’s role through a multi-omics approach to characterize gene expression dynamics and chromatin accessibility changes, coupled with genome-wide identification of FOXL2 targets and on chromatin interacting partners in somatic cells across ovarian development. We found that FOXL2 regulates more targets postnatally, through interaction with factors regulating primordial follicle formation and steroidogenesis. Deletion of one interactor, ubiquitin-specific protease 7 (USP7), results in impairment of somatic cell differentiation, germ cell nest breakdown, and ovarian development, leading to sterility. Our datasets constitute a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.
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Project description:FOXL2 is a transcription factor essential for female fertility, expressed in somatic cells of the ovary, notably granulosa cells. In the mouse, Foxl2 deletion leads to partial sex reversal postnatally, with mutants developing dysgenic ovaries devoid of oocytes. However, deletion of the gene in 8-week-old females leads to granulosa to Sertoli cell transdifferentiation and gonadal sex reversal. We hypothesise that different outcomes of Foxl2 deletion in embryonic versus adult ovary may depend on a different role played by FOXL2 across ovarian development. Therefore, in this study, we take a multi-omics approach to characterise the dynamics of gene expression and chromatin accessibility changes in purified murine granulosa cells across key developmental stages (E14.5, 1 and 8 weeks). We coupled these analyses with genome wide identification of FOXL2 target genes and on-chromatin interacting partners by ChIP-SICAP to reconstruct the gene regulatory networks underpinned by this essential transcription factor and to discover novel players. We found that, in the embryonic ovary, FOXL2 interacts with factors important for early stages of gonadal development, such as GATA4 and WT1, whilst postnatally it interacts with factors regulating primordial follicle activation, such as NR5A2, and with factors regulating steroidogenesis including AR and ESR2. Integration of chromatin landscape dynamics with gene expression changes and FOXL2 binding sites analysis revealed that its critical role in ovarian cell fate maintenance goes beyond repression of the Sertoli-specific gene Sox9. Our chromatome analysis revealed also that FOXL2 interacts with several proteins involved in chromatin remodelling, DNA repair, splicing and gene repression. We identified a FOXL2 interactor with a role in primordial follicle activation, Ubiquitin specific protease 7 (USP7). We showed that conditional deletion of this gene in granulosa cells leads to a blockage of primordial follicle activation, impairs ovary development and leads to complete sterility. In summary, in this study we identified target genes dynamically regulated by FOXL2 across ovarian development including known and newly identified FOXL2 targets with a role in embryonic ovarian development and folliculogenesis, as well as cofactors that point towards additional roles played by FOXL2 besides transcriptional regulation. This work constitutes a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.
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