CREB mediates transient and sustained genomic responses to cAMP via distinct mechanisms [ChIP-seq]

We investigated genome-wide occupancy of CREB, CREB coactivators, lineage determining transcription factors and histone acetylation to uncover mechanisms behind tissue-specific gene induction by cAMP in pancreatic islets. CREB mediates effects of cAMP on cellular gene expression. Most core CREB target genes are ubiquitously induced following recruitment of CREB and its coactivators to promoter proximal binding sites. We found that CREB stimulates the expression of pancreatic beta cell genes by binding to sites within distal enhancers. By contrast with its transient effects on core target genes, CREB stimulates pancreatic beta cell specific gene expression in a sustained manner, reflecting increases in the CBP-mediated acetylation of resident nucleosomes that recruit the chromatin reader BRD4. CREB cooperates with the lineage specific activator Neurod1 in establishing cAMP-responsive enhancers in beta cells. As deletion of a CREB-Neurod1 bound enhancer within the Lrrc10b-Syt7 super-enhancer locus disrupted the expression of both genes and decreased glucose-induced insulin secretion, our results demonstrate how cooperativity between signal dependent and lineage determining factors promotes the expression of cell type-specific gene programs in response to extracellular cues.本研究通过检测环腺苷酸应答元件结合蛋白（CREB）、CREB辅激活因子、谱系决定转录因子及组蛋白乙酰化的全基因组结合占据情况，旨在揭示胰岛中cAMP介导组织特异性基因诱导的分子机制。CREB可介导cAMP对细胞基因表达的调控作用。大多数核心CREB靶基因在CREB及其辅激活因子被招募至启动子近端结合位点后，会被广泛诱导表达。本研究发现，CREB可通过结合远端增强子内的位点，激活胰腺β细胞基因的表达。与对核心靶基因的瞬时调控效应不同，CREB以持续模式激活胰腺β细胞特异性基因的表达，这一过程与CREB结合蛋白（CBP）介导的驻留核小体乙酰化水平升高相关，该乙酰化修饰可招募染色质阅读器溴结构域蛋白4（BRD4）。CREB可与谱系特异性激活因子神经源性分化因子1（Neurod1）协同作用，在β细胞中构建cAMP应答型增强子。当Lrrc10b-Syt7超级增强子位点内的CREB-Neurod1结合增强子被敲除后，这两个基因的表达均受到干扰，且葡萄糖诱导的胰岛素分泌水平下降；本研究结果证实，信号依赖性因子与谱系决定因子之间的协同作用，可响应胞外信号并促进细胞类型特异性基因程序的表达。