The Mina and Everard Goodman Faculty of Life Sciences and the Institute of Nanotechnology and Advanced Materials, Bar-Ilan University, Ramat Gan 5290002, Israel.
Group "Development and Pathology of the Gonad". Department of Genetics, Cell Biology and Development, Institute of Human Genetics, CNRS-University of Montpellier UMR9002, Montpellier, France.
Nucleic Acids Res. 2024 Jun 10;52(10):5514-5528. doi: 10.1093/nar/gkae178.
Male development in mammals depends on the activity of the two SOX gene: Sry and Sox9, in the embryonic testis. As deletion of Enhancer 13 (Enh13) of the Sox9 gene results in XY male-to-female sex reversal, we explored the critical elements necessary for its function and hence, for testis and male development. Here, we demonstrate that while microdeletions of individual transcription factor binding sites (TFBS) in Enh13 lead to normal testicular development, combined microdeletions of just two SRY/SOX binding motifs can alone fully abolish Enh13 activity leading to XY male-to-female sex reversal. This suggests that for proper male development to occur, these few nucleotides of non-coding DNA must be intact. Interestingly, we show that depending on the nature of these TFBS mutations, dramatically different phenotypic outcomes can occur, providing a molecular explanation for the distinct clinical outcomes observed in patients harboring different variants in the same enhancer.
哺乳动物的雄性发育依赖于胚胎睾丸中两个 SOX 基因：Sry 和 Sox9 的活性。由于 Sox9 基因 Enhancer 13（Enh13）的缺失会导致 XY 型雄性向雌性的性反转，我们探索了其功能所必需的关键元件，从而也探索了睾丸和雄性发育所必需的关键元件。在这里，我们证明了 Enh13 中单个转录因子结合位点（TFBS）的微小缺失会导致正常的睾丸发育，而仅仅两个 SRY/SOX 结合基序的微小缺失就可以完全消除 Enh13 的活性，导致 XY 型雄性向雌性的性反转。这表明，为了实现正常的雄性发育，这些少数非编码 DNA 核苷酸必须完整。有趣的是，我们表明，根据这些 TFBS 突变的性质，可以产生截然不同的表型结果，为在同一增强子中携带不同变体的患者观察到的不同临床结果提供了分子解释。
Zotero 插件
