The transcription coactivators CREB binding protein (CBP) and p300 are highly homologous acetyltransferases that mediate histone 3 lysine 27 acetylation (H3K27ac) at regulatory elements such as enhancers and promoters. Although in most cases, CBP and p300 are considered to be functionally identical, both proteins are indispensable for development and there is evidence of tissue-specific nonredundancy. However, characterization of chromatin and transcription states regulated by each protein is lacking. In this study we analyze the individual contribution of p300 and CBP to the H3K27ac landscape, chromatin accessibility, and transcription in mouse embryonic stem cells (mESC). We demonstrate that p300 is the predominant H3K27 acetyltransferase in mESCs and that loss of acetylation in p300KD mESCs is more pronounced at enhancers compared to promoters. While loss of either CBP or p300 has little effect on the open state of chromatin, we observe that distinct gene sets are transcriptionally dysregulated upon depletion of p300 or CBP. Transcriptional dysregulation is generally correlated with dysregulation of promoter acetylation upon depletion of p300 (but not CBP) and appears to be relatively independent of dysregulated enhancer acetylation. Interestingly, both our transcriptional and genomic analyses demonstrate that targets of the p53 pathway are stabilized upon depletion of p300, suggesting an unappreciated view of the relationship between p300 and p53 in mESCs. This genomic study sheds light on distinct functions of two important transcriptional regulators in the context of a developmentally relevant cell type. Given the links to both developmental disorders and cancer, we believe that our study may promote new ways of thinking about how these proteins function in settings that lead to disease.

中文翻译：

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p300和CBP对mESCs调节元件乙酰化的不同贡献。

转录共激活因子CREB结合蛋白（CBP）和p300是高度同源的乙酰基转移酶，可在增强子和启动子等调控元件上介导组蛋白3赖氨酸27乙酰化（H3K27ac）。尽管在大多数情况下，CBP和p300被认为在功能上是相同的，但两种蛋白对于发育都是必不可少的，并且有组织特异性非冗余的证据。但是，缺乏对染色质和每种蛋白质调节的转录状态的表征。在这项研究中，我们分析了p300和CBP对H3K27ac风景，染色质可及性和小鼠胚胎干细胞（mESC）转录的个体贡献。我们证明p300是mESCs中主要的H3K27乙酰转移酶，与启动子相比，p300KD mESCs中乙酰化的损失在增强子上更为明显。虽然CBP或p300的丢失对染色质的开放状态影响很小，但我们观察到，在p300或CBP耗尽后，不同的基因集在转录上失调。转录失调通常与p300耗尽时启动子乙酰化失调相关（但不包括CBP），并且似乎相对独立于增强子乙酰化失调。有趣的是，我们的转录和基因组分析均表明，p53途径的靶点在p300耗尽后就稳定了，这表明mESCs中p300和p53之间关系的观点未被人们理解。这项基因组研究揭示了在发育相关的细胞类型中两个重要转录调节因子的独特功能。鉴于与发育障碍和癌症都有联系，