TET2 catalyzes active DNA demethylation of the Sry promoter and enhances its expression

Sci Rep. 2019 Sep 17;9(1):13462. doi: 10.1038/s41598-019-50058-7.


SRY is the master regulator of male sex determination in eutherian mammals. In mice, Sry expression is transcriptionally and epigenetically controlled in a developmental stage-specific manner. The Sry promoter undergoes demethylation in embryonic gonadal somatic cells at the sex-determining period. However, its molecular mechanism and in vivo significance remain unclear. Here, we report that the Sry promoter is actively demethylated during gonadal development, and TET2 plays a fundamental role in Sry demethylation. Tet2-deficient mice showed absence of 5-hydroxymethylcytosine in the Sry promoter. Furthermore, Tet2 deficiency diminished Sry expression, indicating that TET2-mediated DNA demethylation regulates Sry expression positively. We previously showed that the deficiency of the H3K9 demethylase Jmjd1a compromises Sry expression and induces male-to-female sex reversal. Tet2 deficiency enhanced the sex reversal phenotype of Jmjd1a-deficient mice. Thus, TET2-mediated active DNA demethylation and JMJD1A-mediated H3K9 demethylation contribute synergistically to sex determination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methylcytosine / analogs & derivatives
  • 5-Methylcytosine / metabolism
  • Animals
  • DNA Demethylation*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Dioxygenases
  • Female
  • Gene Expression Regulation, Developmental
  • Gonads* / embryology
  • Male
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Promoter Regions, Genetic*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • Sex Determination Processes
  • Sex-Determining Region Y Protein / genetics*
  • Steroidogenic Factor 1 / metabolism


  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • Sex-Determining Region Y Protein
  • Sry protein, mouse
  • Steroidogenic Factor 1
  • steroidogenic factor 1, mouse
  • 5-hydroxymethylcytosine
  • 5-Methylcytosine
  • Dioxygenases
  • Tet2 protein, mouse