Genome-wide identification of FOXL2 binding and characterization of FOXL2 feminizing action in the fetal gonads

• Published in: Human molecular genetics 2018-12, Vol.27 (24), p.4273-4287
• Main Authors: Nicol, Barbara, Grimm, Sara A, Gruzdev, Artiom, Scott, Greg J, Ray, Manas K, Yao, Humphrey H-C
• Format: Article
• Language: English
• Subjects: Animals; Chromatin - genetics; Female; Fetal Development - genetics; Fetus - metabolism; Forkhead Box Protein L2 - genetics; Gene Expression Regulation, Developmental - genetics; Genome - genetics; Gonads - growth & development; Male; Mice; Ovary - growth & development; Protein Binding; Sex Determination Processes - genetics; Sex Differentiation - genetics; SOX9 Transcription Factor - genetics; Testis - growth & development; Transcriptome - genetics
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddy312

Abstract 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.