Integrative genomic analysis of CREB defines a critical role for transcription factor networks in mediating the fed/fasted switch in liver.
Integrative genomic analysis of CREB defines a critical role for transcription factor networks in mediating the fed/fasted switch in liver.
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DOI：
10.1186/1471-2164-14-337
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发表时间：
2013-05-17
期刊：
影响因子：
4.4
通讯作者：
Kaestner KH
中科院分区：
文献类型：
--
作者：
Everett LJ;Le Lay J;Lukovac S;Bernstein D;Steger DJ;Lazar MA;Kaestner KH
哺乳动物体内的代谢平衡很大程度上依赖于肝脏CREB对禁食诱导基因的调控。以前的全基因组分析表明，只有一小部分CREB靶基因是对禁食相关的信号通路做出反应而诱导的。CREB在荷尔蒙变化的提示下以这些基因为靶标的确切分子机制仍有待阐明。我们对禁食和重新喂养的小鼠的肝脏进行了染色质免疫沉淀和高通量的CREB测序。为了定量比较CREB-DNA在这两种生理状态下的相互作用程度，我们开发了一种新的、稳健的分析方法，称为单样本独立性(SSI)检验，该方法大大减少了假阳性峰的数量。我们发现，无论代谢状态如何，CREB仍然结构性地与其肝脏中的目标基因结合。将CREB序列与禁食和再喂养小鼠肝脏的表达微阵列以及额外转录因子的芯片序列数据整合在一起，揭示了两种代谢状态之间的基因表达切换与CREB位点上额外转录因子的共同定位有关。我们的结果支持这样一个模型，即CREB与数千个靶基因结构性结合，DNA结合因子之间的组合相互作用对于实现肝脏对禁食的特异性转录反应是必要的。此外，我们的全基因组分析在肝脏中发现了数千个新的CREB靶基因，并表明CREB在调节内质网应激基因以响应营养物质内流方面发挥了以前未知的作用。
Metabolic homeostasis in mammals critically depends on the regulation of fasting-induced genes by CREB in the liver. Previous genome-wide analysis has shown that only a small percentage of CREB target genes are induced in response to fasting-associated signaling pathways. The precise molecular mechanisms by which CREB specifically targets these genes in response to alternating hormonal cues remain to be elucidated. We performed chromatin immunoprecipitation coupled to high-throughput sequencing of CREB in livers from both fasted and re-fed mice. In order to quantitatively compare the extent of CREB-DNA interactions genome-wide between these two physiological conditions we developed a novel, robust analysis method, termed the ‘single sample independence’ (SSI) test that greatly reduced the number of false-positive peaks. We found that CREB remains constitutively bound to its target genes in the liver regardless of the metabolic state. Integration of the CREB cistrome with expression microarrays of fasted and re-fed mouse livers and ChIP-seq data for additional transcription factors revealed that the gene expression switches between the two metabolic states are associated with co-localization of additional transcription factors at CREB sites. Our results support a model in which CREB is constitutively bound to thousands of target genes, and combinatorial interactions between DNA-binding factors are necessary to achieve the specific transcriptional response of the liver to fasting. Furthermore, our genome-wide analysis identifies thousands of novel CREB target genes in liver, and suggests a previously unknown role for CREB in regulating ER stress genes in response to nutrient influx.
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影响因子：
29
作者：
Erion DM;Ignatova ID;Yonemitsu S;Nagai Y;Chatterjee P;Weismann D;Hsiao JJ;Zhang D;Iwasaki T;Stark R;Flannery C;Kahn M;Carmean CM;Yu XX;Murray SF;Bhanot S;Monia BP;Cline GW;Samuel VT;Shulman GI
通讯作者：
Shulman GI
影响因子：
29
作者：
Le Lay J;Tuteja G;White P;Dhir R;Ahima R;Kaestner KH
通讯作者：
Kaestner KH
DOI：
10.1038/nrm3072
发表时间：
2011-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
46.9
作者：
Ji, Hongkai;Jiang, Hui;Ma, Wenxiu;Johnson, David S.;Myers, Richard M.;Wong, Wing H.
通讯作者：
Wong, Wing H.
影响因子：
5.3
作者：
Christoffels, VM;Grange, T;Lamers, WH
通讯作者：
Lamers, WH