Genome-wide analysis of acetylated H4K5 binding offers new insights into the acute and chronic effects of METH on gene expression in the dorsal striatum

In contrast to the acute METH-induced transcriptional changes, chronic METH administration produces differential changes in IEG responses and blunts the striatal effects of a single METH injection (McCoy et al., 2011). These observations suggested that chromic METH might have caused changes in the molecular machinery that controls the acute effects of the drug. Gene transcription is regulated by complex interactions of transcription factors with regulatory elements [14,15]. During resting states, DNA is compacted in a way that interferes with the binding of transcription factors whereas DNA becomes more accessible during activation of cells by various stimuli [16]. DNA is indeed packaged into chromatin whose fundamental subunit, the nucleosome, is made of 4 core histones, histones H2A, H2B, H3, and H4 that form an octomer (2 of each histone) surrounded by 146 bp of DNA [17]. The N-tails of histones possess lysine residues that can be reversibly acetylated or deacetylated by several histone acetyltransferases (HATs) or by histone deacetylases (HDACs), respectively [18,19]. These changes promote alterations in gene expression by modifying chromatin conformation and enabling or inhibiting recruitment of regulatory factors onto DNA sequences [20]. Herein, we report that the acute, but not the chronic, transcriptional effects of METH are mediated, for the most part, by increased DNA binding of histone H4 acetylated at lysine 5 (H4K5ac). These results suggest that other factors, including histone and/or DNA methylation, might play a more important role in mediating the molecular effects of chronic METH exposure.与甲基苯丙胺（METH）诱导的急性转录变化不同，慢性甲基苯丙胺给药会对即刻早期基因（IEG）的应答模式产生差异性改变，并削弱单次甲基苯丙胺注射对纹状体的效应（McCoy等，2011）。上述观察结果提示，慢性甲基苯丙胺可能改变了调控该药物急性作用的分子机制。基因转录受转录因子与调控元件之间的复杂相互作用所调控[14,15]。静息状态下，DNA以紧密压缩的构象存在，会干扰转录因子的结合；而当细胞被各类刺激激活时，DNA的可及性会显著提升[16]。DNA确实会被包装为染色质，其基本结构亚基为核小体（nucleosome）：核小体由4种核心组蛋白（H2A、H2B、H3、H4）构成八聚体（每种组蛋白各2个拷贝），外绕146 bp的DNA序列[17]。组蛋白的N端尾区含有赖氨酸残基，可分别通过多种组蛋白乙酰转移酶（HATs）或组蛋白去乙酰化酶（HDACs）进行可逆的乙酰化或去乙酰化修饰[18,19]。这类修饰通过改变染色质构象，调控调控因子在DNA序列上的招募与结合，进而影响基因表达[20]。本研究发现，甲基苯丙胺的急性（而非慢性）转录效应，主要通过赖氨酸5位乙酰化的组蛋白H4（H4K5ac）的DNA结合能力增强所介导。上述结果提示，包括组蛋白和/或DNA甲基化在内的其他因素，可能在介导慢性甲基苯丙胺暴露的分子效应中发挥更为关键的作用。