A cellular model of the oncogenic FOXL2 somatic pathogenic variant C134W provides new insights in pathogenicity
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE225781 | GEO | 2024/02/22
REPOSITORIES: GEO
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Project description:In order to identify genes misregulated by the adult OGCT-associated FOXL2 p.C134ZW mutant in granulosa cells, we have transfected COV434 cells (negative for the mutation) using an expression vector containing the wildtype or mutant coding sequence of FOXL2 or, as a reference, the empty vector pcDNA. The transcriptome perturbation induced by FOXL2 overexpression was then followed by DNA microarray using a platform developed by NimbleGen Systems, Inc.
2013-03-06 | E-MTAB-1017 | biostudies-arrayexpress
Project description:We have generated a humanized Foxl2 mouse model by genome editing to evaluate in vivo the role of mutated FOXL2 in the development of murine Adult Granulosa Cell Tumors
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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:From fish to human, FOXL2 is considered one of the most conserved markers of ovarian granulosa cell identity. To determine if the sole expression of FOXL2 can determine ovarian differentiation, we created a mouse model that allows the conditional expression of FOXL2. Rosa26-CAG-LSL-Foxl2 mice were crossed to Sf1-Cre mice to induce the expression of FOXL2 in the SF1+ somatic cells of the fetal gonads.When FOXL2 was induced in the somatic cells of the undifferentiated testis, the Sertoli cells and consequently the other cell lineages composing the fetal gonads were feminized, resulting in a partial testis-to-ovary sex reversal We created a mouse genetic model that conditionaly express FOXL2 in the somatic cells of the fetal gonads. All embryos used in this study resulted from the crossing between Rosa26-CAG-LSL-Foxl2+/f and Sf1-cre+/Tg mice. XX and XY fetal gonads were collected at embryonic day E14.5. This microarray analysis led to the identification of the genes misregulated upon ectopic induction of FOXL2 in the fetal testis, and showed that FOXL2 expression resulted in feminization of both somatic and germ cells of the fetal gonad.
2019-03-25 | GSE78774 | GEO
Project description:It has previously been shown that FOXL2 and ESR1 cooperate to repress the testis-determining gene Sox9 in murine granulosa cells, and suggested that FOXL2/ESR1 cooperation may be central to granulosa cell differentiation (Uhlenhaut et al., 2009). However, no study has so far compared the DNA-binding of FOXL2 and ESR1 at the genomic level or analyzed the impact of FOXL2 on ESR1 binding to its regulatory elements. Here, we have analyzed and compared the genomic locations recognized by ESR1 and FOXL2 in E2-treated primary murine granulosa cells. Input DNA, FOXL2 and ESR1 ChIP
2015-07-01 | E-GEOD-62545 | biostudies-arrayexpress
Project description:It has previously been shown that FOXL2 and ESR1 cooperate to repress the testis-determining gene Sox9 in murine granulosa cells, and suggested that FOXL2/ESR1 cooperation may be central to granulosa cell differentiation (Uhlenhaut et al., 2009). However, no study has so far compared the DNA-binding of FOXL2 and ESR1 at the genomic level or analyzed the impact of FOXL2 on ESR1 binding to its regulatory elements. Here, we have analyzed and compared the genomic locations recognized by ESR1 and FOXL2 in E2-treated primary murine granulosa cells.
2015-07-01 | GSE62545 | GEO
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: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.
2022-07-11 | PXD024439 | Pride
Project description:To investigate the targets of FOXL2 in human granulosa cells, we performed Knock-Down experiment in established homozygous cell lines for FOXL2 WT (KGN).
2023-11-06 | GSE227040 | GEO
Project description:The identity of the gonads is determined by which fate, ovarian granulosa cell or testicular Sertoli cell, the bipotential somatic cell precursors choose to follow. In most vertebrates, the fate of granulosa cells is controlled by a conserved regulator FOXL2. To understand how FOXL2 elicits its fate-determining action, we performed genome-wide analysis of FOXL2 chromatin occupancy in fetal ovaries. Combining genome-wide analysis of FOXL2 binding in the fetal ovary with transcriptomic analyses of Foxl2 gain-of-function and Foxl2 loss-of-function models, we identified potential pathways responsible for the feminizing action of FOXL2. Finally, comparison of FOXL2 genome-wide occupancy in the fetal ovary with testis-determining factor SOX9 genome-wide occupancy in the fetal testis revealed extensive overlaps, implying that antagonistic signals between FOXL2 and SOX9 occur at the chromatin level.
2019-03-21 | GSE110093 | GEO