Transcriptome sequencing revealed that knocking down FOXL2 affected cell proliferation, the cell cycle, and DNA replication in chicken pre-ovulatory follicle cells

Luo, Wei; Gu, Lantao; Li, Jinqiu; Gong, Yanzhang

doi:10.1371/journal.pone.0234795

Cited by 18 publications

(11 citation statements)

References 34 publications

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“…The analysis of our RNA‐seq data pointed to many DE genes involved in important ovarian processes, consistent with our previous observations 1 . In agreement with data obtained in the chicken ovary, we also found that long‐term Foxl2 depletion in murine cells affects the expression of genes involved in cell proliferation and the cell cycle (Supplementary Table 4) 15 . We also uncovered new potential pathways regulated by FOXL2 such as cellular senescence and insulin resistance (Supplementary Table 3 and Supplementary Table 4).…”

Section: Discussionsupporting

confidence: 92%

“…Transcriptomic profiling of AGCTs has shown that genes differentially expressed (DE) between tumors and control samples are enriched in FOXL2 targets and bear several hallmarks of cancer, such as decreased sensitivity to cell death and stimulation of cell proliferation 11 . This is consistent with work implicating FOXL2 in the control of cell cycle, apoptosis, DNA repair, 12‐14 and with more recent data where a knockdown of FOXL2 in chicken granulosa cells was found to affect cell proliferation, DNA replication, apoptosis and cell cycle progression 15 …”

Section: Introductionsupporting

confidence: 82%

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Genomic exploration of the targets of FOXL2 and ESR2 unveils their implication in cell migration, invasion, and adhesion

et al. 2021

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FOXL2 and ESR2 are key transcriptional regulators in ovarian granulosa cells. To explore their transcriptional roles and their interplay, we have depleted Foxl2 and Esr2 in mouse primary granulosa cells to assess their ability to bind their targets and/or to modulate gene expression and cellular functions. We show that FOXL2 is involved in a large number of regulatory actions essential for the maintenance of granulosa cell fate. A parallel ChIP-seq analysis showed that FOXL2 mainly binds to sites located in intergenic regions quite far from its targets. A bioinformatic analysis demonstrated that FOXL2-activated genes were enriched in peaks associated with the H3K27ac mark, whereas FOXL2-repressed genes were not, suggesting that FOXL2 can activate transcription through binding to enhancer sites. We also identified about 500 deregulated genes upon Esr2 silencing, of which one third are also targets of FOXL2. We provide evidence showing that both factors modulate, through a coherent feed-forward loop, a number of common targets. Many of the FOXL2/ESR2 targets are involved in cell motility and, consistently, granulosa cells depleted for either Foxl2 or Esr2 exhibit decreased migration, invasion and adhesion. This effect is paralleled by the depletion of their target Phactr1, involved in actin cytoskeleton dynamics. Our analysis expands the number of direct and indirect transcriptional targets of both FOXL2 and ESR2, which deserve investigation in the context of adult-type granulosa cell tumors whose molecular diagnostic hallmark is the presence of the C134W FOXL2 pathogenic variant.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionsupporting

confidence: 82%

Genomic exploration of the targets of FOXL2 and ESR2 unveils their implication in cell migration, invasion, and adhesion

et al. 2021

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“…FOXL2 is a core transcription factor that maintains the identity of granulosa cells, and it has extensive functions through the regulation of the expression of genes in different signaling pathways. In our previous studies, when Foxl2 was overexpressed (Wang, 2017) or knocked down through small interfering RNA (Luo Wei, 2020), the genes involved in the ECM interaction pathways were up‐ or downregulated. Collagens are one of the main components in the ECM, and this research provides the first report that FOXL2 affects the expression of total collagen in chicken follicular granulosa cells in different developmental stages.…”

Section: Discussionmentioning

confidence: 99%

FOXL2 regulates the expression of the Col4a1 collagen gene in chicken granulosa cells

Guo

et al. 2022

Molecular Reproduction Devel

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Forkhead box L2 (FOXL2), one member in the superfamily of forkhead transcription factors, is a core transcription factor specifically expressed in ovarian granulosa cells and is essential for the development of follicles. FOXL2 has been shown to regulate the transcription of genes encoding enzymes that synthesize steroid hormones and estrogen receptors and regulate the expression of collagen genes in granulosa cells. This study explored the effect of FOXL2 on collagen gene expression in granulosa cells by overexpressing Foxl2 in pregranulosa cells, prehierarchical follicles and preovulation follicle granulosa cells. The results showed that FOXL2 regulated the expression of several genes encoding collagens in chicken granulosa cells and that overexpression of Foxl2 significantly reduced the messenger RNA and protein levels of Col4a1 in different granulosa cells. Moreover, luciferase reporter and chromatin immunoprecipitation assays were performed to study how FOXL2 regulates the expression of collagen genes, and the results showed that FOXL2 directly regulated the expression of Col4a1 by binding to the motif of CAGCAGCACCAGCAG between −640 and −625 bp upstream of the coding region. The results indicated that FOXL2 could regulate the components of the extracellular matrix; however, the biological significance of this regulation needs further clarification.

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“…Establishment of a granulosa cell culture and siRNA-mediated knockdown of the androgen receptor in granulosa cells were performed according to previously described methods ( Luo et al, 2020 ). The target sequence of AR-siRNA is GGTTGGAGATCTTTCACTA.…”

Section: Methodsmentioning

confidence: 99%

Comparative Analysis Among Different Species Reveals That the Androgen Receptor Regulates Chicken Follicle Selection Through Species-Specific Genes Related to Follicle Development

Huang

Luo

et al. 2022

Front. Genet.

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The differences in reproductive processes at the molecular level between viviparous and oviparous animals are evident, and the site in the ovary that synthesizes sex hormones (androgens and oestrogens) and the trends for enriching sex hormones during follicle development in chickens are different from those in mammals, suggesting that the effect of sex hormones on follicle development in chickens is probably different from that in viviparous animals. To explore the specific role of androgen receptors (ARs) on chicken follicular development, we matched the correspondence of follicular development stages among chickens, humans, cows and identified chicken-specific genes related to follicle development (GAL-SPGs) by comparing follicle development-related genes and their biological functions among species (chickens, humans, and cows). A comparison of the core transcription factor regulatory network of granulosa cells (or ovaries) based on super-enhancers among species (chicken, human, and mouse) revealed that AR is a core transcriptional regulator specific to chickens. In vivo experiments showed that inhibition of AR significantly reduced the number of syf (selected stage follicles) in chickens and decreased the expression of GAL-SPGs in F5 follicles, while in vitro experiments showed that inhibition of AR expression in chicken granulosa cells (GCs) significantly down-regulated the expression levels of GAL-SPGs, indicating that AR could regulate follicle selection through chicken-specific genes related to follicle development. A comparison among species (77 vertebrates) of the conserved genomic regions, where chicken super-enhancers are located, revealed that the chicken AR super-enhancer region is conserved in birds, suggesting that the role of AR in follicle selection maybe widespread in birds. In summary, we found that AR can regulate follicle selection through chicken-specific genes related to follicle development, which also emphasizes the important role of AR in follicle selection in chickens and provides a new perspective for understanding the unique process of follicle development in chickens. Our study will contribute to the application of androgens to the control of egg production in chickens and suggests that researchers can delve into the mechanisms of follicle development in birds based on androgen/androgen receptors.

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Transcriptome sequencing revealed that knocking down FOXL2 affected cell proliferation, the cell cycle, and DNA replication in chicken pre-ovulatory follicle cells

Cited by 18 publications

References 34 publications

Genomic exploration of the targets of FOXL2 and ESR2 unveils their implication in cell migration, invasion, and adhesion

Genomic exploration of the targets of FOXL2 and ESR2 unveils their implication in cell migration, invasion, and adhesion

FOXL2 regulates the expression of the Col4a1 collagen gene in chicken granulosa cells

Comparative Analysis Among Different Species Reveals That the Androgen Receptor Regulates Chicken Follicle Selection Through Species-Specific Genes Related to Follicle Development

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