Global Genome Analysis of the Downstream Binding Targets of Testis Determining Factor SRY and SOX9

Abstract

A major event in mammalian male sex determination is the induction of the testis determining factor Sry and its downstream gene Sox9. The current study provides one of the first genome wide analyses of the downstream gene binding targets for SRY and SOX9 to help elucidate the molecular control of Sertoli cell differentiation and testis development. A modified ChIP-Chip analysis using a comparative hybridization was used to identify 71 direct downstream binding targets for SRY and 109 binding targets for SOX9. Interestingly, only 5 gene targets overlapped between SRY and SOX9. In addition to the direct response element binding gene targets, a large number of atypical binding gene targets were identified for both SRY and SOX9. Bioinformatic analysis of the downstream binding targets identified gene networks and cellular pathways potentially involved in the induction of Sertoli cell differentiation and testis development. The specific DNA sequence binding site motifs for both SRY and SOX9 were identified. Observations provide insights into the molecular control of male gonadal sex determination.

AP-1 family members act with Sox9 to promote chondrocyte hypertrophy

“…By contrast, when Sox9 and AP-1 engage together through their cognate DNA-target sequence, their combined actions elevate expression above levels induced by either factor alone. Given our recent findings (Ohba et al, 2015) and those of other groups (Bhandari et al, 2012;Liu and Lefebvre, 2015;Oh et al, 2014Oh et al, , 2010 that the transcription of Sox9-specific chondrocyte targets is governed by integrating information from multiple independent enhancer elements, the overall impact of AP-1 factor activation on any given Sox9/AP-1 target gene is not easy to predict as it will reflect the combined action of multiple binding activities within any given enhancer and the integration of information from multiple enhancers; the inhibitory action of protein-protein interactions could function to fine-tune expression of target genes. However, the balance of the evidence herein suggests that the combined action of AP-1 factor input promotes a progressive hypertrophic chondrocyte program with Sox9.…”

SOX9 drives WNT pathway activation in prostate cancer

“…23 and Figure 1D). Recent SOX9 ChIP studies in other cell types have similarly found substantial divergence from the SOX9 consensus motif (24)(25)(26).…”

Expression profile of the SOX9 gene in the testes of sexually immature and mature male goats (Capra hircus), and its potential influence on postnatal testis development

“…The HMG domain binds to consensus sites in the regulatory regions of its target genes, and thus is the most important with respect to target gene expression. SOX9 is a factor with multiple functions in organogenesis (Bhandari et al 2012), among which testis induction and formation are crucial for interpreting the results of the present study. A discussion regarding the transcriptional activity of this determinant of the male developmental pathway should focus on two important aspects.…”

“…An analogous situation is observed in the case of potential target genes of SOX9. Although it is accepted that its major target is the anti-Mullerian hormone (AMH) promoter, the latest research conducted on rats has shown that there are over 100 genes with consensus binding sites for SOX9 (Bhandari et al 2012). Th e main regulator initiating SOX9 transcriptional activity via TESCO in the primitive male gonads is SRY.…”