G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis

Makoto Tachibana; Kenji Sugimoto; Masami Nozaki; Jun Ueda; Tsutomu Ohta; Misao Ohki; Mikiko Fukuda; Naoki Takeda; Hiroyuki Niida; Hiroyuki Kato; Yoichi Shinkai

doi:10.1101/gad.989402

G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis

¹Department of Cell Biology, Institute for Virus Research, Kyoto University, Shogoin Kawara-cho, Kyoto 606-8507, Japan; ²Laboratory of Applied Molecular Biology, Department of Applied Biochemistry, Osaka Prefecture University, Osaka 599-8501, Japan; ³Research Institute for Microbial Disease, Osaka University, Osaka 565-0871, Japan; ⁴Medical Genomics Center, National Cancer Center Research Institute, Tokyo 104-0045, Japan; ⁵Department of Oncology, Nippon Roche Research Center, Kamakura 247-0063, Japan; ⁶National Institute of Infectious Diseases, Musashimurayama, Tokyo 208-0011, Japan

Abstract

Covalent modification of histone tails is crucial for transcriptional regulation, mitotic chromosomal condensation, and heterochromatin formation. Histone H3 lysine 9 (H3-K9) methylation catalyzed by the Suv39h family proteins is essential for establishing the architecture of pericentric heterochromatin. We recently identified a mammalian histone methyltransferase (HMTase), G9a, which has strong HMTase activity towards H3-K9 in vitro. To investigate the in vivo functions of G9a, we generated G9a-deficient mice and embryonic stem (ES) cells. We found that H3-K9 methylation was drastically decreased in G9a-deficient embryos, which displayed severe growth retardation and early lethality. G9a-deficient ES cells also exhibited reduced H3-K9 methylation compared to wild-type cells, indicating that G9a is a dominant H3-K9 HMTase in vivo. Importantly, the loss of G9a abolished methylated H3-K9 mostly in euchromatic regions. Finally, G9a exerted a transcriptionally suppressive function that depended on its HMTase activity. Our results indicate that euchromatic H3-K9 methylation regulated by G9a is essential for early embryogenesis and is involved in the transcriptional repression of developmental genes.

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Footnotes

Present addresses: ⁷Center for Animal Resources and Development, Kumamoto University, Kumamoto 860-0811, Japan; ⁸Department of Biochemistry, Nagoya City University Medical School, Nagoya 467-8601, Japan.
↵9 Corresponding author.
E-MAIL yshinkai{at}virus.kyoto-u.ac.jp; FAX 81-75-751-3991.
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.989402.
- Received March 5, 2002.
- Accepted May 22, 2002.
Cold Spring Harbor Laboratory Press