Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence.
Gene coexpression networks in human brain identify epigenetic modifications in alcohol dependence.
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DOI：
10.1523/jneurosci.3136-11.2012
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发表时间：
2012-02-01
期刊：
影响因子：
--
通讯作者：
Mayfield RD
中科院分区：
文献类型：
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作者：
Ponomarev I;Wang S;Zhang L;Harris RA;Mayfield RD
酒精滥用导致人类大脑中基因表达的广泛变化，其中一些导致酒精依赖。以前的微阵列研究确定了个体基因作为酒精表型的候选者，但缺乏对酒精成瘾潜在的分子和细胞变化的综合看法。在这里，我们应用了一种新的系统方法，在死后的人类大脑中进行转录组分析，并生成了与酒精滥用相关的大脑改变的系统视图。我们确定了关键的细胞成分和以前未被认识到的基因共表达关系的表观遗传决定因素，并发现了酒精脑中染色质修饰的新标记。酗酒者中内源性逆转录病毒和GC含量高的基因的高表达水平与DNA低甲基化和组蛋白H3K4三甲基化增加相关，表明表观遗传机制在酒精成瘾中的关键作用。对细胞类型特异性转录组的分析揭示了酒精中毒脑中分子谱和细胞异常之间的显著一致性。基于这项研究和其他研究的证据，我们产生了一个系统假说，染色质修饰在酒精依赖中的核心作用，整合了基因表达的表观遗传调控与酒精大脑的病理生理和神经适应性变化。我们的研究结果为酒精和药物成瘾的表观遗传治疗提供了启示。
Alcohol abuse causes widespread changes in gene expression in human brain, some of which contribute to alcohol dependence. Previous microarray studies identified individual genes as candidates for alcohol phenotypes, but efforts to generate an integrated view of molecular and cellular changes underlying alcohol addiction are lacking. Here, we applied a novel systems approach to transcriptome profiling in postmortem human brains and generated a systemic view of brain alterations associated with alcohol abuse. We identified critical cellular components and previously unrecognized epigenetic determinants of gene co-expression relationships and discovered novel markers of chromatin modifications in alcoholic brain. Higher expression levels of endogenous retroviruses and genes with high GC content in alcoholics were associated with DNA hypomethylation and increased histone H3K4 tri-methylation, suggesting a critical role of epigenetic mechanisms in alcohol addiction. Analysis of cell type – specific transcriptomes revealed remarkable consistency between molecular profiles and cellular abnormalities in alcoholic brain. Based on evidence from this study and others, we generated a systems hypothesis for the central role of chromatin modifications in alcohol dependence that integrates epigenetic regulation of gene expression with pathophysiological and neuroadaptive changes in alcoholic brain. Our results offer implications for epigenetic therapeutics in alcohol and drug addiction.