Epigenetic control of SOX9 gene by the histone acetyltransferase P300 in human Sertoli cells

• Published in: Heliyon Vol. 10; no. 12; p. e33173
• Main Authors: González, Daniel, Peña, María José, Bernal, Camila, García-Acero, Mary, Manotas, Maria Carolina, Suarez-Obando, Fernando, Rojas, Adriana
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 30.06.2024; Elsevier
• Subjects: Disorders of sexual development (DSD); Epigenetics; Histone modifications; P300; Sertoli; SOX9; Transcriptional control; Sertoli; P300; Epigenetics; Histone modifications; SOX9; Transcriptional control; Disorders of sexual development (DSD)
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2024.e33173

The transcription factor SOX9 is a key regulator of male sexual development and Sertoli cell differentiation. Altered SOX9 expression has been implicated in the pathogenesis of disorders of sexual development (DSD) in mammals. However, limited information exists regarding the epigenetic mechanisms governing its transcriptional control during sexual development. This study employed real-time PCR (qPCR), immunofluorescence (IIF), and chromatin immunoprecipitation (ChIP) assays to investigate the epigenetic mechanisms associated with SOX9 gene transcriptional control in human and mouse Sertoli cell lines. To identify the specific epigenetic enzymes involved in SOX9 epigenetic control, functional assays using siRNAs for P300, GCN5, and WDR5 were performed. The transcriptional activation of SOX9 was associated with selective deposition of active histone modifications, such as H3K4me3 and H3K27ac, at its enhancer and promoter regions. Importantly, the histone acetyltransferase P300 was found to be significantly enriched at the SOX9 enhancers, co-localizing with the H3K27ac and the SOX9 transcription factor. Silencing of P300 led to decreased SOX9 expression and reduced H3K27ac levels at the eSR-A and e-ALDI enhancers, demonstrating the crucial role of P300-mediated histone acetylation in SOX9 transcriptional activation. Interestingly, another histone lysine acetyltransferases like GNC5 and methyltransferases as the Trithorax/COMPASS-like may also have a relevant role in male sexual differentiation. Histone acetylation by P300 at SOX9 enhancers, is a key mechanism governing the transcriptional control of this essential regulator of male sexual development. These findings provide important insights into the epigenetic basis of sexual differentiation and the potential pathogenesis of DSDs. [Display omitted] •The presence of H3K4me3, H3K9ac and H3K27ac at its promoter and enhancer regions mediates SOX9 transcriptional activation.•P300 is a key regulator of SOX9's epigenetic switch, methylating H3K27ac at eSR-A and e-ALDI to activate SOX9 transcription.•Histone modifications are involved in sexual differentiation through epigenetic control of SOX9.