Two redundant transcription factor binding sites in a single enhancer are essential for mammalian sex determination

Meshi Ridnik, Elisheva Abberbock, Veronica Alipov, Shelly Ziv Lhermann, Shoham Kaufman, Maor Lubman, Francis Poulat, Nitzan Gonen

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)5514-5528
Number of pages15
JournalNucleic Acids Research
Volume52
Issue number10
DOIs
StatePublished - 10 Jun 2024

Bibliographical note

Publisher Copyright:
© 2024 The Author(s). Published by Oxford University Press on behalf of Nucleic Acids Research.

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