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

TLDR

Covalent histone tail modifications regulate transcription, chromosome condensation, and heterochromatin, with H3‑K9 methylation by Suv39h proteins essential for pericentric heterochromatin architecture. The study aimed to elucidate G9a’s in vivo role by generating G9a‑deficient mice and embryonic stem cells. G9a‑deficient mice and embryonic stem cells were created to evaluate the impact of G9a loss on H3‑K9 methylation and embryonic development. Loss of G9a dramatically reduces H3‑K9 methylation, especially in euchromatin, causing severe growth retardation, early embryonic lethality, and transcriptional repression of developmental genes, confirming G9a as the dominant in vivo H3‑K9 methyltransferase.

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.