Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London WC1E 6DD, UK.
Neuron. 2012 Apr 12;74(1):122-35. doi: 10.1016/j.neuron.2012.02.021.
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.
据信，染色质的活性依赖性修饰有助于神经元回路的巨大变化。这些修饰的机制尚不完全清楚。组蛋白变体 H3.3 以复制独立的方式被掺入基因组的不同区域，包括基因调控元件。目前尚不清楚 H3.3 的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 在调节活性依赖性基因座处 H3.3 掺入中的作用。发现 DAXX 与选定的活性调节基因的调控区相关联，在那里它促进了膜去极化时 H3.3 的加载。DAXX 的缺失不仅影响 H3.3 的沉积，而且还损害了这些基因的转录诱导。钙调神经磷酸酶介导的 DAXX 去磷酸化是控制其在神经元激活时功能的关键分子开关。总的来说，这些发现表明 H3.3 伴侣 DAXX 参与了活性依赖性事件的调节，从而揭示了神经元中表观遗传修饰的新机制。
