CHARGE syndrome-associated proteins FAM172A and CHD7 influence male sex determination and differentiation through transcriptional and alternative splicing mechanisms

FASEB J. 2022 Mar;36(3):e22176. doi: 10.1096/fj.202100837RR.


To gain further insight into chromatin-mediated regulation of mammalian sex determination, we analyzed the role of the CHARGE syndrome-associated proteins FAM172A and CHD7. This study is based on our prior discoveries that a subset of corresponding mutant mice display complete male-to-female sex reversal, and that both of these proteins regulate co-transcriptional alternative splicing in neural crest cells. Here, we report that FAM172A and CHD7 are present in the developing gonads when sex determination normally occurs in mice. The interactome of FAM172A in pre-Sertoli cells again suggests a role at the chromatin-spliceosome interface, like in neural crest cells. Accordingly, analysis of Fam172a-mutant pre-Sertoli cells revealed transcriptional and splicing dysregulation of hundreds of genes. Many of these genes are similarly affected in Chd7-mutant pre-Sertoli cells, including several known key regulators of sex determination and subsequent formation of testis cords. Among them, we notably identified Sry as a direct transcriptional target and WNT pathway-associated Lef1 and Tcf7l2 as direct splicing targets. The identified molecular defects are also associated with the abnormal morphology of seminiferous tubules in mutant postnatal testes. Altogether, our results thus identify FAM172A and CHD7 as new players in the regulation of male sex determination and differentiation in mice, and further highlight the importance of chromatin-mediated regulatory mechanisms in these processes.

Keywords: CHARGE syndrome; CHD7; FAM172A; Sex reversal; alternative splicing; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing*
  • Animals
  • CHARGE Syndrome / genetics*
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Developmental
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Proteins / genetics
  • Proteins / metabolism*
  • Sertoli Cells / metabolism
  • Sex Determination Processes*
  • Spermatogenesis
  • Swine
  • Transcriptome*


  • Chd7 protein, mouse
  • DNA-Binding Proteins
  • Fam172a protein, mouse
  • Proteins