Abstract
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 language | English |
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Pages (from-to) | 1035-1054 |
Number of pages | 20 |
Journal | Genes and Development |
Volume | 35 |
Issue number | 13 |
DOIs | |
Publication status | Published - 1 Jul 2021 |
Externally published | Yes |
Keywords
- Epigenetics
- G9a
- H3K9me2
- Noncoding RNA
- Tsix
- X chromosome inactivation
- Xist
ASJC Scopus subject areas
- Genetics
- Developmental Biology