Reproductive and Developmental Biology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Integrative Bioinformatics Support Group, National Institute of Environmental Health Sciences, Research Triangle Park, NC, USA.
Hum Mol Genet. 2018 Dec 15;27(24):4273-4287. doi: 10.1093/hmg/ddy312.
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 conserved transcription factor FOXL2 contributes to the fate of granulosa cells. To understand FOXL2 functions during gonad differentiation, we performed genome-wide analysis of FOXL2 chromatin occupancy in fetal ovaries and established a genetic mouse model that forces Foxl2 expression in the fetal testis. When FOXL2 was ectopically expressed in the somatic cell precursors in the fetal testis, FOXL2 was sufficient to repress Sertoli cell differentiation, ultimately resulting in partial testis-to-ovary sex-reversal. Combining genome-wide analysis of FOXL2 binding in the fetal ovary with transcriptomic analyses of our Foxl2 gain-of-function and previously published 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.
性腺的身份由哪种命运决定，是卵巢颗粒细胞还是睾丸支持细胞，双潜能体细胞前体选择遵循的命运。在大多数脊椎动物中，保守的转录因子 FOXL2 有助于颗粒细胞的命运。为了了解 FOXL2 在性腺分化过程中的功能，我们对胎儿卵巢中 FOXL2 染色质占据的全基因组进行了分析，并建立了一种遗传小鼠模型，该模型迫使 Foxl2 在胎儿睾丸中表达。当 FOXL2 在胎儿睾丸中的体细胞前体中异位表达时，FOXL2 足以抑制支持细胞的分化，最终导致部分睾丸到卵巢性别反转。将 FOXL2 在胎儿卵巢中的结合的全基因组分析与我们的 Foxl2 功能获得和以前发表的 Foxl2 功能丧失模型的转录组分析相结合，我们确定了潜在的途径，这些途径负责 FOXL2 的女性化作用。最后，将 FOXL2 在胎儿卵巢中的全基因组占据与睾丸决定因子 SOX9 在胎儿睾丸中的全基因组占据进行比较，发现广泛重叠，这意味着 FOXL2 和 SOX9 之间的拮抗信号发生在染色质水平。
