Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues
Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues
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DOI：
10.1073/pnas.0501076102
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发表时间：
2005-03-22
影响因子：
11.1
通讯作者：
Montminy, M
中科院分区：
文献类型：
--
作者：
Zhang, XM;Odom, DT;Montminy, M
激素和营养素通常通过与基因特异性激活剂相互作用的信号通路诱导遗传程序。例如，cAMP途径的激活通过PKA介导的cAMP反应元件结合蛋白（CREB）在Ser-133的磷酸化刺激细胞基因表达。在这里，我们使用全基因组的方法来表征在不同的细胞环境中由CREB调控的靶基因。CREB被发现在体内占据大约4，000个启动子位点，这取决于启动子附近共有cAMP反应元件的存在和甲基化状态。CREB占用的配置文件是非常相似的，在不同的人体组织中，和暴露于cAMP激动剂刺激CREB磷酸化超过大多数这些网站。然而，在任何细胞类型中，只有一小部分CREB靶基因被cAMP诱导，部分原因是共激活因子CREB结合蛋白优先募集到这些启动子。这些结果表明，单独的CREB磷酸化不是靶基因激活的可靠预测因子，并且需要额外的CREB调节伴侣来将转录装置募集到启动子。
Hormones and nutrients often induce genetic programs via signaling pathways that interface with gene-specific activators. Activation of the cAMP pathway, for example, stimulates cellular gene expression by means of the PKA-mediated phosphorylation of cAMP-response element binding protein (CREB) at Ser-133. Here, we use genome-wide approaches to characterize target genes that are regulated by CREB in different cellular contexts. CREB was found to occupy approximate to 4,000 promoter sites in vivo, depending on the presence and methylation state of consensus cAMP response elements near the promoter. The profiles for CREB occupancy were very similar in different human tissues, and exposure to a cAMP agonist stimulated CREB phosphorylation over a majority of these sites. Only a small proportion of CREB target genes was induced by cAMP in any cell type, however, due in part to the preferential recruitment of the coactivator CREB-binding protein to those promoters. These results indicate that CREB phosphorylation alone is not a reliable predictor of target gene activation and that additional CREB regulatory partners are required for recruitment of the transcriptional apparatus to the promoter.