Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading and transcription upon neuronal activation.
Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading and transcription upon neuronal activation.
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DOI：
10.1016/j.neuron.2012.02.021
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发表时间：
2012-04-12
期刊：
影响因子：
16.2
通讯作者：
Salomoni P
中科院分区：
文献类型：
--
作者：
Michod D;Bartesaghi S;Khelifi A;Bellodi C;Berliocchi L;Nicotera P;Salomoni P
染色质的活性依赖性修饰被认为有助于神经元回路的戏剧性变化。这些变化背后的机制尚不完全清楚。组蛋白变体H3.3以一种不依赖复制的方式被整合到基因组的不同区域，包括基因调控元件。目前尚不清楚H3.3沉积是否参与神经元活动依赖性事件。在这里，我们分析了组蛋白伴侣DAXX在调节H3.3在活性依赖基因位点的结合中的作用。发现DAXX与选定的活性调节基因的调控区域相关，在那里它促进H3.3在膜去极化时的负载。DAXX缺失不仅影响H3.3沉积，还会损害这些基因的转录诱导。钙调磷酸酶介导的DAXX去磷酸化是控制其神经元激活功能的关键分子开关。总之，这些发现暗示H3.3伴侣DAXX参与活动依赖性事件的调节，从而揭示了神经元表观遗传修饰的新机制。►神经元激活诱导H3.3在eggs的调控元件上负载►H3.3在选定的eggs的调控区域沉积依赖于DAXX►DAXX调节选定的eggs的转录诱导►DAXX的功能受钙调磷酸酶的控制表观遗传修饰可通过组蛋白变体的沉积发生。Michod等人提出了中枢神经系统中组蛋白变体H3.3的动态、活性依赖性替代和转录调控的机制。
Activity-dependent modifications of chromatin are believed to contribute to dramatic changes in neuronal circuitry. The mechanisms underlying these modifications are not fully understood. The histone variant H3.3 is incorporated in a replication-independent manner into different regions of the genome, including gene regulatory elements. It is presently unknown whether H3.3 deposition is involved in neuronal activity-dependent events. Here, we analyze the role of the histone chaperone DAXX in the regulation of H3.3 incorporation at activity-dependent gene loci. DAXX is found to be associated with regulatory regions of selected activity-regulated genes, where it promotes H3.3 loading upon membrane depolarization. DAXX loss not only affects H3.3 deposition but also impairs transcriptional induction of these genes. Calcineurin-mediated dephosphorylation of DAXX is a key molecular switch controlling its function upon neuronal activation. Overall, these findings implicate the H3.3 chaperone DAXX in the regulation of activity-dependent events, thus revealing a new mechanism underlying epigenetic modifications in neurons. ► Neuronal activation induces H3.3 loading at regulatory elements of IEGs ► H3.3 deposition at regulatory regions of selected IEGs is dependent on DAXX ► DAXX regulates transcriptional induction of selected IEGs ► DAXX function is under the control of calcineurin Epigenetic modification can occur through deposition of histone variants. Michod et al. propose a mechanism underlying dynamic, activity-dependent replacement of the histone variant H3.3 and transcriptional regulation in the central nervous system.
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