Enhancer Histone Acetylation Modulates Transcriptional Bursting Dynamics of Neuronal Activity-Inducible Genes
Enhancer Histone Acetylation Modulates Transcriptional Bursting Dynamics of Neuronal Activity-Inducible Genes
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DOI：
10.1016/j.celrep.2019.01.032
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发表时间：
2019-01-29
期刊：
影响因子：
8.8
通讯作者：
West, Anne E.
中科院分区：
文献类型：
--
作者：
Chen, Liang-Fu;Lin, Yen Ting;West, Anne E.
神经元活动诱导的基因转录与活动调节基因启动子和增强子处组蛋白乙酰化的快速和短暂增加相关。组蛋白乙酰化究竟如何调节这些基因的转录仍然是未知的。我们使用单细胞原位转录分析表明，Fos和Npas 4在小鼠神经元中的随机突发中转录，并且膜去极化通过增加突发频率来增加mRNA表达。然后，我们表达dCas 9-p300或dCas 9-HDAC 8融合蛋白以模拟或阻断增强子处局部活性诱导的组蛋白乙酰化。添加组蛋白乙酰化通过延长爆发持续时间增加Fos转录，并导致更高的Fos蛋白水平和静息膜电位升高。抑制组蛋白乙酰化通过降低爆发频率和体内海马中受损的经验依赖性Fos蛋白诱导来降低Fos转录。因此，活动诱导的组蛋白乙酰化调节的经验调节基因的转录动力学，影响神经元基因表达和细胞功能的选择性变化。
Neuronal activity-inducible gene transcription correlates with rapid and transient increases in histone acetylation at promoters and enhancers of activity-regulated genes. Exactly how histone acetylation modulates transcription of these genes has remained unknown. We used single-cell in situ transcriptional analysis to show that Fos and Npas4 are transcribed in stochastic bursts in mouse neurons and that membrane depolarization increases mRNA expression by increasing burst frequency. We then expressed dCas9-p300 or dCas9-HDAC8 fusion proteins to mimic or block activity-induced histone acetylation locally at enhancers. Adding histone acetylation increased Fos transcription by prolonging burst duration and resulted in higher Fos protein levels and an elevation of resting membrane potential. Inhibiting histone acetylation reduced Fos transcription by reducing burst frequency and impaired experience-dependent Fos protein induction in the hippocampus in vivo. Thus, activity-inducible histone acetylation tunes the transcriptional dynamics of experience-regulated genes to affect selective changes in neuronal gene expression and cellular function.