28 research outputs found
CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila Polycomb silencing
Trimethylation of histone H3 lysine 27 (H3K27me3) by Polycomb repressive
complex 2 (PRC2) is essential for transcriptional silencing of Polycomb target
genes, whereas acetylation of H3K27 (H3K27ac) has recently been shown to be
associated with many active mammalian genes. The Trithorax protein (TRX),
which associates with the histone acetyltransferase CBP, is required for
maintenance of transcriptionally active states and antagonizes Polycomb
silencing, although the mechanism underlying this antagonism is unknown. Here
we show that H3K27 is specifically acetylated by Drosophila CBP and
its deacetylation involves RPD3. H3K27ac is present at high levels in early
embryos and declines after 4 hours as H3K27me3 increases. Knockdown of E(Z)
decreases H3K27me3 and increases H3K27ac in bulk histones and at the promoter
of the repressed Polycomb target gene abd-A, suggesting that these
indeed constitute alternative modifications at some H3K27 sites. Moderate
overexpression of CBP in vivo causes a global increase in H3K27ac and a
decrease in H3K27me3, and strongly enhances Polycomb mutant phenotypes. We
also show that TRX is required for H3K27 acetylation. TRX overexpression also
causes an increase in H3K27ac and a concomitant decrease in H3K27me3 and leads
to defects in Polycomb silencing. Chromatin immunoprecipitation coupled with
DNA microarray (ChIP-chip) analysis reveals that H3K27ac and H3K27me3 are
mutually exclusive and that H3K27ac and H3K4me3 signals coincide at most
sites. We propose that TRX-dependent acetylation of H3K27 by CBP prevents
H3K27me3 at Polycomb target genes and constitutes a key part of the molecular
mechanism by which TRX antagonizes or prevents Polycomb silencing