Nuclear Receptor Biology Section, CEB, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
EMBO J. 2011 Jan 19;30(2):249-62. doi: 10.1038/emboj.2010.318. Epub 2010 Dec 3.
Histone acetyltransferases (HATs) GCN5 and PCAF (GCN5/PCAF) and CBP and p300 (CBP/p300) are transcription co-activators. However, how these two distinct families of HATs regulate gene activation remains unclear. Here, we show deletion of GCN5/PCAF in cells specifically and dramatically reduces acetylation on histone H3K9 (H3K9ac) while deletion of CBP/p300 specifically and dramatically reduces acetylations on H3K18 and H3K27 (H3K18/27ac). A ligand for nuclear receptor (NR) PPARδ induces sequential enrichment of H3K18/27ac, RNA polymerase II (Pol II) and H3K9ac on PPARδ target gene Angptl4 promoter, which correlates with a robust Angptl4 expression. Inhibiting transcription elongation blocks ligand-induced H3K9ac, but not H3K18/27ac, on the Angptl4 promoter. Finally, we show GCN5/PCAF and GCN5/PCAF-mediated H3K9ac correlate with, but are surprisingly dispensable for, NR target gene activation. In contrast, CBP/p300 and their HAT activities are essential for ligand-induced Pol II recruitment on, and activation of, NR target genes. These results highlight the substrate and site specificities of HATs in cells, demonstrate the distinct roles of GCN5/PCAF- and CBP/p300-mediated histone acetylations in gene activation, and suggest an important role of CBP/p300-mediated H3K18/27ac in NR-dependent transcription.
组蛋白乙酰转移酶（HATs）GCN5 和 PCAF（GCN5/PCAF）和 CBP 和 p300（CBP/p300）是转录共激活因子。然而，这两种不同家族的 HATs 如何调节基因激活仍不清楚。在这里，我们显示细胞特异性缺失 GCN5/PCAF 会显著降低组蛋白 H3K9（H3K9ac）的乙酰化，而特异性缺失 CBP/p300 会显著降低 H3K18 和 H3K27（H3K18/27ac）的乙酰化。核受体（NR）PPARδ 的配体诱导 H3K18/27ac、RNA 聚合酶 II（Pol II）和 H3K9ac 在 PPARδ 靶基因 Angptl4 启动子上的顺序富集，这与 Angptl4 的表达增强相关。抑制转录延伸会阻断配体诱导的 Angptl4 启动子上的 H3K9ac，但不阻断 H3K18/27ac。最后，我们发现 GCN5/PCAF 和 GCN5/PCAF 介导的 H3K9ac 与 NR 靶基因激活相关，但令人惊讶的是，GCN5/PCAF 是 NR 靶基因激活所必需的。相比之下，CBP/p300 及其 HAT 活性对于配体诱导的 Pol II 在 NR 靶基因上的募集和激活是必不可少的。这些结果突出了细胞中 HATs 的底物和位点特异性，证明了 GCN5/PCAF 和 CBP/p300 介导的组蛋白乙酰化在基因激活中的独特作用，并提示了 CBP/p300 介导的 H3K18/27ac 在 NR 依赖性转录中的重要作用。
