A disproportionate impact of G9a methyltransferase deficiency on the X chromosome
- Attila Szanto1,2,
- Rodrigo Aguilar1,2,
- Barry Kesner1,2,
- Roy Blum1,2,
- Danni Wang1,2,
- Catherine Cifuentes-Rojas1,2,
- Brian C. del Rosario1,2,
- Katalin Kis-Toth3 and
- Jeannie T. Lee1,2
- 1Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA;
- 2Department of Genetics, The Blavatnik Institute, Harvard Medical School, Boston, Massachusetts 02115, USA;
- 3Department of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School Boston, Massachusetts 02115, USA
- Corresponding author: lee{at}molbio.mgh.harvard.edu
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 show that 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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.337592.120.
- Received February 12, 2020.
- Accepted May 27, 2021.
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