Biliński Przemysław, Wojtyła Andrzej, Kapka-Skrzypczak Lucyna, Chwedorowicz Roman, Cyranka Małgorzata, Studziński Tadeusz
Chief Sanitary Inspectorate, and Institute of Haematology and Transfusion Medicine, Warsaw, Poland.
Ann Agric Environ Med. 2012;19(3):491-6.
The interaction between environmental signals and genes has now taken on a clear molecular form as demonstrated by stable changes in chromatin structure. These changes occur through activation or repression of specific gene programmes by a combination of chromatin remodelling, activation and enzymatic modification of DNA and histones as well as nucleosomal subunit exchange. Recent research investigating the molecular mechanisms controlling drug-induced transcriptional, behavioural and synaptic activity has shown a direct role for chromatin remodelling--termed as epigenetic regulation--of neuronal gene programmes and subsequent addictive behaviour arising from it. Recent data suggest that repeated exposure to certain drugs promotes changes in levels of histone acetylation, phosphorylation and methylation, together with alterations in DNA methylation levels in the neurons of the brain reward centre, localised in the Nucleus Accumbens (NAc) region of the limbic system. The combination of acetylating, phosphorylating and methylating H3 and H4 histone tails alter chromatin compaction thereby promoting altered levels of cellular gene expression. Histone modifications, which weaken histone interaction with DNA or that promote recruitment of transcriptional activating complexes, correlate with permissive gene expression. Histone deacetylation, (which strengthen histone: DNA contacts), or histone methylation, (which recruits repressive complexes to chromatin), promote a state of transcriptional repression. Using animal models, acute cocaine treatment increases H4 acetylation at acutely regulated gene promoters, whereas H3 acetylation appears to predominate at chronically induced promoters. Chronic cocaine and alcohol treatment activate and repress many genes such as FosB, Cdk5, and Bdnf, where their dysregulation, at the chromatin level, contribute to the development and maintenance of addiction. Following drug exposure, it is still unknown, howver, how long these changes in chromatin structure persist in affecting neuronal function, but some do so for life.
环境信号与基因之间的相互作用如今已呈现出清晰的分子形式，染色质结构的稳定变化便是明证。这些变化是通过染色质重塑、DNA和组蛋白的激活与酶促修饰以及核小体亚基交换等多种方式，对特定基因程序进行激活或抑制而发生的。近期有关控制药物诱导的转录、行为及突触活动分子机制的研究表明，染色质重塑（即表观遗传调控）在神经元基因程序以及由此产生的成瘾行为中发挥着直接作用。近期数据显示，反复接触某些药物会促使大脑奖赏中枢（位于边缘系统伏隔核区域）神经元中的组蛋白乙酰化、磷酸化和甲基化水平发生变化，同时DNA甲基化水平也会改变。H3和H4组蛋白尾部的乙酰化、磷酸化和甲基化相结合会改变染色质的紧实度，从而促使细胞基因表达水平发生改变。削弱组蛋白与DNA相互作用或促进转录激活复合物募集的组蛋白修饰，与允许性基因表达相关。组蛋白去乙酰化（增强组蛋白与DNA的接触）或组蛋白甲基化（将抑制性复合物募集至染色质）会促进转录抑制状态。利用动物模型研究发现，急性可卡因处理会增加急性调控基因启动子处的H4乙酰化，而H3乙酰化似乎在慢性诱导启动子处占主导。慢性可卡因和酒精处理会激活和抑制许多基因，如FosB、Cdk5和Bdnf，它们在染色质水平的失调会导致成瘾的发展和维持。然而，药物暴露后，这些染色质结构变化在影响神经元功能方面会持续多久仍不明确，但有些变化会持续终生。
