FOXL2 interaction with different binding partners regulates the dynamics of granulosa cell differentiation across ovarian development [RNA-Seq]
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ABSTRACT:
PROVIDER: PRJNA992538 | ENA |
REPOSITORIES: ENA
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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.
2024-03-25 | PXD043951 | Pride
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.
2024-03-24 | GSE236785 | GEO
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.
2024-03-24 | GSE236859 | GEO
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.
2024-03-24 | GSE236860 | GEO
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.
2024-03-24 | GSE236862 | GEO
Project description:FOXL2 interaction with different binding partners regulates the dynamics of ovarian development
| PRJNA992534 | ENA
Project description:FOXL2 interaction with different binding partners regulates the dynamics of granulosa cell differentiation across ovarian development [ATAC-Seq]
| PRJNA992428 | ENA
Project description:FOXL2 interaction with different binding partners regulates the dynamics of granulosa cell differentiation across ovarian development [ChIP-Seq]
| PRJNA992537 | ENA
Project description:The Foxl2 transcription factor is required for ovarian function during follicular development. Our approach to begin to understand Foxl2 function is through the identification of Foxl2 regulated genes in the ovary. Transiently transfected KK1 mouse granulosa cells were used to identify genes that are potentially regulated by Foxl2. KK1 cells were transfected in three groups (mock, activated, and repressed) and twenty-four hours later RNA was isolated and submitted for Affymetrix microarray analysis. Experiment Overall Design: To increase the potential of Foxl2 to alter gene expression levels of putative target genes, two fusions were constructed consisting of Foxl2 fused to the activation domain of the Herpes simplex virus VP16 transcription factor (Foxl2-VP16) and Foxl2 fused to the repression domain of the murine MAD transcription factor (Foxl2-MAD). Levels of gene expression were compared between mock transfected cells and those that were transfected with Foxl2-VP16 and Foxl2-MAD, respectively.
2009-11-15 | E-GEOD-18891 | biostudies-arrayexpress
Project description:The Foxl2 transcription factor is required for ovarian function during follicular development. Our approach to begin to understand Foxl2 function is through the identification of Foxl2 regulated genes in the ovary. Transiently transfected KK1 mouse granulosa cells were used to identify genes that are potentially regulated by Foxl2. KK1 cells were transfected in three groups (mock, activated, and repressed) and twenty-four hours later RNA was isolated and submitted for Affymetrix microarray analysis.
2009-11-05 | GSE18891 | GEO