Histone Hypervariants H2A.Z.1 and H2A.Z.2 Play Independent and Context-Specific Roles in Neuronal Activity-Induced Transcription of Arc/Arg3.1 and Other Immediate Early Genes.
Histone Hypervariants H2A.Z.1 and H2A.Z.2 Play Independent and Context-Specific Roles in Neuronal Activity-Induced Transcription of Arc/Arg3.1 and Other Immediate Early Genes.
复制标题
组蛋白高变量H2A.Z.1和H2A.Z.2在神经元活性诱导的ARC/ARG3.1和其他直接早期基因的转录中起独立和上下文特异性的作用。
DOI：
10.1523/eneuro.0040-17.2017
复制
发表时间：
2017-07
期刊：
影响因子：
3.4
通讯作者：
Saha RN
中科院分区：
文献类型：
--
作者：
Dunn CJ;Sarkar P;Bailey ER;Farris S;Zhao M;Ward JM;Dudek SM;Saha RN
组蛋白变体 H2A.Z 是真核基因转录的重要且保守的调节因子。然而，这种组蛋白在转录过程中的确切作用仍然令人困惑。在脊椎动物中，H2A.Z 有两个超变体：H2A.Z.1 和 H2A.Z.2，除了三个氨基酸残基外，它们具有几乎相同的序列。由于这种相似性，这些超变体在神经生物学过程中的功能特异性（如果有的话）在很大程度上仍然未知。在这项针对分离的大鼠皮质神经元的研究中，我们询问 H2A.Z 超变体在调节基础基因转录和活动诱导的基因转录方面是否具有独特的功能。高变体特异性 RNAi 和微阵列分析表明，H2A.Z.1 和 H2A.Z.2 调节大部分不重叠基因集的基础表达，包括编码几种突触蛋白的基因。为了响应神经元活动，我们的模型基因 Arc 的快速转录会因 H2A.Z.2 的耗尽而受到损害，但 H2A.Z.1 不会受到损害。这种损伤可以通过 H2A.Z 伴侣 ANP32E 的共缺失得到部分缓解。相反，在不同的环境下（河豚毒素，TTX 48 小时后），Arc 的快速转录因任一超变体的耗尽而受到损害。正如我们的多重基因表达测定所揭示的，H2A.Z 超变体的这种背景依赖性作用在其他几个立即早期基因中也很明显，其中这些超变体的调节作用在不同条件下因基因而异。总之，我们的数据表明 H2A.Z 超变体具有特定背景的作用，它们相互补充以介导活动诱导的神经元基因转录。
The histone variant H2A.Z is an essential and conserved regulator of eukaryotic gene transcription. However, the exact role of this histone in the transcriptional process remains perplexing. In vertebrates, H2A.Z has two hypervariants, H2A.Z.1 and H2A.Z.2, that have almost identical sequences except for three amino acid residues. Due to such similarity, functional specificity of these hypervariants in neurobiological processes, if any, remain largely unknown. In this study with dissociated rat cortical neurons, we asked if H2A.Z hypervariants have distinct functions in regulating basal and activity-induced gene transcription. Hypervariant-specific RNAi and microarray analyses revealed that H2A.Z.1 and H2A.Z.2 regulate basal expression of largely nonoverlapping gene sets, including genes that code for several synaptic proteins. In response to neuronal activity, rapid transcription of our model gene Arc is impaired by depletion of H2A.Z.2, but not H2A.Z.1. This impairment is partially rescued by codepletion of the H2A.Z chaperone, ANP32E. In contrast, under a different context (after 48 h of tetrodotoxin, TTX), rapid transcription of Arc is impaired by depletion of either hypervariant. Such context-dependent roles of H2A.Z hypervariants, as revealed by our multiplexed gene expression assays, are also evident with several other immediate early genes, where regulatory roles of these hypervariants vary from gene to gene under different conditions. Together, our data suggest that H2A.Z hypervariants have context-specific roles that complement each other to mediate activity-induced neuronal gene transcription.