Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
Mol Cell Biol. 2012 Jun;32(12):2323-34. doi: 10.1128/MCB.06392-11. Epub 2012 Apr 9.
Trithorax group (TrxG) proteins antagonize Polycomb silencing and are required for maintenance of transcriptionally active states. We previously showed that the Drosophila melanogaster acetyltransferase CREB-binding protein (CBP) acetylates histone H3 lysine 27 (H3K27ac), thereby directly blocking its trimethylation (H3K27me3) by Polycomb repressive complex 2 (PRC2) in Polycomb target genes. Here, we show that H3K27ac levels also depend on other TrxG proteins, including the histone H3K27-specific demethylase UTX and the chromatin-remodeling ATPase Brahma (BRM). We show that UTX and BRM are physically associated with CBP in vivo and that UTX, BRM, and CBP colocalize genome-wide on Polycomb response elements (PREs) and on many active Polycomb target genes marked by H3K27ac. UTX and BRM bind directly to conserved zinc fingers of CBP, suggesting that their individual activities are functionally coupled in vivo. The bromodomain-containing C terminus of BRM binds to the CBP PHD finger, enhances PHD binding to histone H3, and enhances in vitro acetylation of H3K27 by recombinant CBP. brm mutations and knockdown of UTX by RNA interference (RNAi) reduce H3K27ac levels and increase H3K27me3 levels. We propose that direct binding of UTX and BRM to CBP and their modulation of H3K27ac play an important role in antagonizing Polycomb silencing.
三价组蛋白 (TrxG) 蛋白拮抗多梳抑制，并需要维持转录活跃状态。我们之前表明，黑腹果蝇乙酰转移酶 CREB 结合蛋白 (CBP) 乙酰化组蛋白 H3 赖氨酸 27 (H3K27ac)，从而直接阻止其多梳抑制复合物 2 (PRC2) 在多梳靶基因中三甲基化 (H3K27me3)。在这里，我们表明 H3K27ac 水平也依赖于其他 TrxG 蛋白，包括组蛋白 H3K27 特异性去甲基酶 UTX 和染色质重塑 ATP 酶 Brahma (BRM)。我们表明，UTX 和 BRM 在体内与 CBP 物理相关，并且 UTX、BRM 和 CBP 在全基因组上在多梳反应元件 (PREs) 上以及在许多由 H3K27ac 标记的活性多梳靶基因上共定位。UTX 和 BRM 直接结合到 CBP 的保守锌指上，这表明它们的个体活性在体内功能上是耦合的。BRM 的含有溴结构域的 C 末端结合到 CBP 的 PHD 指上，增强 PHD 与组蛋白 H3 的结合，并增强重组 CBP 对 H3K27ac 的体外乙酰化作用。brm 突变和 RNA 干扰 (RNAi) 敲低 UTX 降低了 H3K27ac 水平并增加了 H3K27me3 水平。我们提出，UTX 和 BRM 与 CBP 的直接结合及其对 H3K27ac 的调节在拮抗多梳抑制中起着重要作用。
