JOURNAL ARTICLE

A mutation in the E(Z) methyltransferase that increases trimethylation of histone H3 lysine 27 and causes inappropriate silencing of active Polycomb target genes

Vincent A Stepanik, Peter J Harte
Developmental Biology 2012 April 15, 364 (2): 249-58
22182520
Drosophila Polycomb Repressive Complex 2 (PRC2) is a lysine methyltransferase that trimethylates histone H3 lysine 27 (H3K27me3), a modification essential for Polycomb silencing. Mutations in its catalytic subunit, E(Z), that abolish its methyltransferase activity disrupt Polycomb silencing, causing derepression of Polycomb target genes in cells where they are normally silenced. In contrast, the unusual E(z) mutant allele Trithorax mimic (E(z)(Trm)) causes dominant homeotic phenotypes similar to those caused by mutations in trithorax (trx), an antagonist of Polycomb silencing. This suggests that E(z)(Trm) causes inappropriate silencing of Polycomb target genes in cells where they are normally active. Here we show that E(z)(Trm) mutants have an elevated level of H3K27me3 and reduced levels of H3K27me1 and H3K27me2, modifications also carried out by E(Z). This suggests that the E(z)(Trm) mutation increases the H3K27 trimethylation efficiency of E(Z). Acetylated H3K27 (H3K27ac), a mark of transcriptionally active genes that directly antagonizes H3K27 methylation by E(Z), is also reduced in E(z)(Trm) mutants, consistent with their elevated H3K27me3 level causing inappropriate silencing. In 0-4h E(z)(Trm) embryos, H3K27me3 accumulates prematurely and to high levels and does so at the expense of H3K27ac, which is normally present at high levels in early embryos. Despite their high level of H3K27me3, expression of Abd-B initiates normally in homozygous E(z)(Trm) embryos, but is substantially lower than in wild type embryos by completion of germ band retraction. These results suggest that increased H3K27 trimethylation activity of E(Z)(Trm) causes the premature accumulation of H3K27me3 in early embryogenesis, "predestining" initially active Polycomb target genes to silencing once Polycomb silencing is initiated.

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