title: Synergistic effect of SRY and its direct target, WDR5, on Sox9 expression.
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.
authors.affiliation: The State Key Laboratory of Pharmaceutical Biotechnology, Molecular Immunology and Cancer Research Center, School of Life Sciences, Nanjing University, Nanjing, China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xu
authors.forename: Xinxing
authors.initials: X
authors.lastname: Gao
authors.forename: Yinghong
authors.initials: Y
authors.lastname: He
authors.forename: Junyi
authors.initials: J
authors.lastname: Ju
authors.forename: Miaomiao
authors.initials: M
authors.lastname: Zhang
authors.forename: Ronghua
authors.initials: R
authors.lastname: Liu
authors.forename: Yupeng
authors.initials: Y
authors.lastname: Wu
authors.forename: Chunyan
authors.initials: C
authors.lastname: Ma
authors.forename: Chi
authors.initials: C
authors.lastname: Ma
authors.forename: Zhaoyu
authors.initials: Z
authors.lastname: Lin
authors.forename: Xingxu
authors.initials: X
authors.lastname: Huang
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhao
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms; D011506:Proteins / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000096:biosynthesis*; D051876:Sex-Determining Region Y Protein / Q000378:metabolism*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000494:pharmacology; D013737:Testis / Q000196:embryology* / Q000378:metabolism; D051176:beta Catenin / Q000096:biosynthesis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D055758:SOX9 Transcription Factor; D051876:Sex-Determining Region Y Protein; C502547:WDR5 protein, human; C443118:Wdr5 protein, mouse; D051176:beta Catenin; D013629:Tamoxifen; C016601:afimoxifene; D011495:Histone-Lysine N-Methyltransferase