Two redundant transcription factor binding sites in a single enhancer are essential for mammalian sex determination.
Nucleic Acids Res
; 52(10): 5514-5528, 2024 Jun 10.
Article
in En
| MEDLINE
| ID: mdl-38499491
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Enhancer Elements, Genetic
/
Sex Determination Processes
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Nucleic Acids Res
Year:
2024
Document type:
Article
Affiliation country:
Israel