A disproportionate impact of G9a methyltransferase deficiency on the X chromosome

Attila Szanto, Rodrigo Aguilar, Barry Kesner, Roy Blum, Danni Wang, Catherine Cifuentes-Rojas, Brian C. del Rosario, Katalin Kis-Toth, Jeannie T. Lee

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)


G9a is a histone methyltransferase responsible for the dimethylation of histone H3 at lysine 9 (H3K9me2). G9a plays key roles in transcriptional silencing of developmentally regulated genes, but its role in X-chromosome inactivation (XCI) has been under debate. Here, we uncover a female-specific function of G9a and demonstrate that deleting G9a has a disproportionate impact on the X chromosome relative to the rest of the genome. G9a deficiency causes a failure of XCI and female-specific hypersensitivity to drug inhibition of H3K9me2. We showthat G9a interacts with Tsix and Xist RNAs, and that competitive inhibition of the G9a-RNA interaction recapitulates the XCI defect. During XCI, Xist recruits G9a to silence X-linked genes on the future inactive X. In parallel on the future Xa, Tsix recruits G9a to silence Xist in cis. Thus, RNA tethers G9a for allele-specific targeting of the H3K9me2 modification and the G9a-RNA interaction is essential for XCI.

Original languageEnglish
Pages (from-to)1035-1054
Number of pages20
JournalGenes and Development
Issue number13
Publication statusPublished - 1 Jul 2021
Externally publishedYes


  • Epigenetics
  • G9a
  • H3K9me2
  • Noncoding RNA
  • Tsix
  • X chromosome inactivation
  • Xist

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology


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