Abstract
SRY is a sex-determining gene that encodes a transcription factor, which triggers male development in most mammals. The molecular mechanism of SRY action in testis determination is, however, poorly understood. In this study, we demonstrate that WDR5, which encodes a WD-40 repeat protein, is a direct target of SRY. EMSA experiments and ChIP assays showed that SRY could bind to the WDR5 gene promoter directly. Overexpression of SRY in LNCaP cells significantly increased WDR5 expression concurrent with histone H3K4 methylation on the WDR5 promoter. To specifically address whether SRY contributes to WDR5 regulation, we introduced a 4-hydroxy-tamoxifen-inducible SRY allele into LNCaP cells. Conditional SRY expression triggered enrichment of SRY on the WDR5 promoter resulting in induction of WDR5 transcription. We found that WDR5 was self regulating through a positive feedback loop. WDR5 and SRY interacted and were colocalized in cells. In addition, the interaction of WDR5 with SRY resulted in activation of Sox9 while repressing the expression of β-catenin. These results suggest that, in conjunction with SRY, WDR5 plays an important role in sex determination.
Highlights
WDR5, named BIG-3, was first identified in a murine prechondroblastic cell line by differential display PCR following induction with BMP-2
WDR5 is a member of the WD-40 repeat protein family, which exhibits a seven-bladed propeller-like structure with a narrow channel running through the center [2,3]
WDR5 is a core subunit of MLL/SET1 complexes, it functions as a subunit of other complexes
Summary
WDR5, named BIG-3, was first identified in a murine prechondroblastic cell line by differential display PCR following induction with BMP-2. WDR5 has been shown to be a regulator of embryonic stem cell self-renewal, and its expression correlates with the undifferentiated state [6]. It is not known how WDR5 itself is regulated. SRY, a member of the Sox (SRY-related HMG box) gene family, interacts with CaM (calmodulin) and importin b and facilitates translocation of proteins from cytoplasm to nucleus [11,12]. The interaction of WDR5 and SRY activates Sox expression. As Sox is the master regulator of sex determination [18,19], we hypothesize that WDR5 interacts with SRY to promote testis development
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