Abstract
Mammalian histone methyltransferase G9a (also called EHMT2) deposits H3K9me2 on chromatin and is essential for postimplantation development. However, its role in oogenesis and preimplantation development remains poorly understood. We show that H3K9me2-enriched chromatin domains in mouse oocytes are generally depleted of CG methylation, contrasting with their association in embryonic stem and somatic cells. Oocyte-specific disruption of G9a results in reduced H3K9me2 enrichment and impaired reorganization of heterochromatin in oocytes, but only a modest reduction in CG methylation is detected. Furthermore, in both oocytes and 2-cell embryos, G9a depletion has limited impact on the expression of genes and retrotransposons. Although their CG methylation is minimally affected, preimplantation embryos derived from such oocytes show abnormal chromosome segregation and frequent developmental arrest. Our findings illuminate the functional importance of G9a independent of CG methylation in preimplantation development and call into question the proposed role for H3K9me2 in CG methylation protection in zygotes.
Highlights
G9a is a mammalian histone methyltransferase that mediates dimethylation of lysine 9 of core histone H3 (H3K9me2) with its catalytic SET domain (Tachibana et al, 2001, 2002; Collins et al, 2005)
We reprocessed published RNA sequencing (RNA-seq) data from wild-type oocytes (Veselovska et al, 2015) and found that it is expressed at low levels in early growing oocytes (GOs) and progressively upregulated in late GOs and fully grown oocytes (FGOs) (Figure S1A)
It has been reported that GOs progressively accumulate H3K9me2 (Kageyama et al, 2007)
Summary
G9a ( known as EHMT2) is a mammalian histone methyltransferase that mediates dimethylation of lysine 9 of core histone H3 (H3K9me2) with its catalytic SET domain (Tachibana et al, 2001, 2002; Collins et al, 2005). The protein forms a heterodimer with a structurally related G9a-like protein (GLP, known as EHMT1), whose SET domain mediates H3K9me deposition on chromatin (Tachibana et al, 2002, 2005). In mouse embryonic stem cells (ESCs) and primary somatic tissues, such as liver and brain, H3K9me2-enriched chromatin domains (up to 5 Mb) have been identified (Wen et al, 2009). Within such domains, a negative correlation between H3K9me deposition and gene expression is observed (Wen et al, 2009). These domains are highly conserved between human and mouse and often overlap with nuclear lamina-associated domains (LADs) (Wen et al, 2009; Kind et al, 2013)
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