Bose Daniel A, Donahue Greg, Reinberg Danny, Shiekhattar Ramin, Bonasio Roberto, Berger Shelley L
Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Department of Molecular Pharmacology and Biochemistry, New York University School of Medicine, New York, NY 10016, USA.
Cell. 2017 Jan 12;168(1-2):135-149.e22. doi: 10.1016/j.cell.2016.12.020.
CBP/p300 are transcription co-activators whose binding is a signature of enhancers, cis-regulatory elements that control patterns of gene expression in multicellular organisms. Active enhancers produce bi-directional enhancer RNAs (eRNAs) and display CBP/p300-dependent histone acetylation. Here, we demonstrate that CBP binds directly to RNAs in vivo and in vitro. RNAs bound to CBP in vivo include a large number of eRNAs. Using steady-state histone acetyltransferase (HAT) assays, we show that an RNA binding region in the HAT domain of CBP-a regulatory motif unique to CBP/p300-allows RNA to stimulate CBP's HAT activity. At enhancers where CBP interacts with eRNAs, stimulation manifests in RNA-dependent changes in the histone acetylation mediated by CBP, such as H3K27ac, and by corresponding changes in gene expression. By interacting directly with CBP, eRNAs contribute to the unique chromatin structure at active enhancers, which, in turn, is required for regulation of target genes.
CBP/p300是转录共激活因子，其结合是增强子的一个标志，增强子是控制多细胞生物中基因表达模式的顺式调控元件。活跃的增强子产生双向增强子RNA（eRNA）并表现出CBP/p300依赖性组蛋白乙酰化。在这里，我们证明CBP在体内和体外都能直接与RNA结合。在体内与CBP结合的RNA包括大量的eRNA。使用稳态组蛋白乙酰转移酶（HAT）分析，我们表明CBP的HAT结构域中的一个RNA结合区域——CBP/p300特有的调控基序——允许RNA刺激CBP的HAT活性。在CBP与eRNA相互作用的增强子处，刺激表现为CBP介导的组蛋白乙酰化的RNA依赖性变化，如H3K27ac，以及基因表达的相应变化。通过直接与CBP相互作用，eRNA有助于活跃增强子处独特的染色质结构，而这反过来又是调控靶基因所必需的。
