Epigenetic control of OX9 gene by the histone acetyltransferase P300 in human Sertoli cells.

BACKGROUND

The transcription factor SOX9 is a key regulator of male sexual development and Sertoli cell differentiation. Altered OX9 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.

METHODS

This study employed real-time PCR (qPCR), immunofluorescence (IIF), and chromatin immunoprecipitation (ChIP) assays to investigate the epigenetic mechanisms associated with OX9 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.

RESULTS

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.

CONCLUSIONS

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.