A calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression.
A calcium-dependent switch in a CREST-BRG1 complex regulates activity-dependent gene expression.
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DOI：
10.1016/j.neuron.2008.09.040
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发表时间：
2008-12-10
期刊：
影响因子：
16.2
通讯作者：
Ghosh A
中科院分区：
文献类型：
--
作者：
Qiu Z;Ghosh A
依赖活动的基因表达在调节感觉体验对神经系统发育和功能的影响中起着重要作用。虽然已经确定了几种活性依赖的转录因子，但钙信号将启动子从沉默状态转变为活性状态的机制尚不清楚。在这里，我们证明了CREST-BRG1复合体在调节启动子激活中起关键作用，它通过协调抑制物复合体的钙依赖释放和激活物复合体的招募来调节启动子的激活。在静息神经元中，c-fos启动子的转录被依赖于BRG1的磷酸化-Rb-HDAC抑制复合体的招募所抑制。当钙内流时，Rb在丝氨酸795位被钙调神经磷酸酶去磷酸化，导致阻遏复合体的释放。同时，CBP通过一种依赖于CREST的机制增加了对启动子的招募，从而导致转录激活。CREST-BRG1还与NR2B启动子结合，活性依赖的NR2B表达诱导涉及HDAC1的释放和CBP的募集，表明这一机制可能普遍参与调节神经元基因的钙依赖转录。
Activity-dependent gene expression plays an important role in mediating the effects of sensory experience on nervous system development and function. While several activity-dependent transcription factors have been identified, the mechanism by which calcium signaling converts a promoter from a silenced to an active state is not well understood. Here we show that a CREST-BRG1 complex plays a critical role in regulating promoter activation by orchestrating a calcium-dependent release of a repressor complex, and a recruitment of an activator complex. In resting neurons, transcription of the c-fos promoter is inhibited by BRG1-dependent recruitment of a phospho-Rb-HDAC repressor complex. Upon calcium influx, Rb becomes dephosphorylated at Serine 795 by Calcineurin, which leads to release of the repressor complex. At the same time there is increased recruitment of CBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 also binds to the NR2B promoter and activity-dependent induction of NR2B expression involves a release of HDAC1 and recruitment of CBP, suggesting that this mechanism may be generally involved in regulating calcium-dependent transcription of neuronal genes.
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