Vaissière Thomas, Sawan Carla, Herceg Zdenko
Epigenetics Group, International Agency for Research on Cancer (IARC), 150 Cours Albert-Thomas, F-69008 Lyon, France.
Mutat Res. 2008 Jul-Aug;659(1-2):40-8. doi: 10.1016/j.mrrev.2008.02.004. Epub 2008 Feb 29.
Knowledge on heritable changes in gene expression that result from epigenetic events is of increasing relevance in the development of strategies for prevention, early diagnosis and treatment of cancer. Histone acetylation and DNA methylation are epigenetic modifications whose patterns can be regarded as heritable marks that ensure accurate transmission of the chromatin states and gene expression profiles over many cell generations. Importantly, patterns and levels of DNA methylation and histone acetylation are profoundly altered in human cancers. Accumulating evidence suggests that an epigenetic cross-talk, i.e. interplay between DNA methylation and histone acetylation, may be involved in the process of gene transcription and aberrant gene silencing in tumours. Although the molecular mechanism of gene activation is relatively well understood, the hierarchical order of events and dependencies leading to gene silencing in the course of cancer development remain largely unknown. While some studies suggest that DNA methylation patterns guide histone modifications (including histone acetylation and methylation) during gene silencing, other studies argue that DNA methylation takes its cues primarily from histone modification states. In this review, we summarize current knowledge on the interplay between DNA methylation and histone modifications during gene silencing and its importance in the integration of environmental and intrinsic stimuli in the control of gene expression. We also discuss the importance of an epigenetic cross-talk in the protection against genetic changes in response to environmental genotoxins as well as the implication for cancer therapy and prevention.
关于由表观遗传事件导致的基因表达可遗传变化的知识，在癌症预防、早期诊断和治疗策略的制定中越来越重要。组蛋白乙酰化和DNA甲基化是表观遗传修饰，其模式可被视为可遗传标记，确保染色质状态和基因表达谱在许多细胞世代中准确传递。重要的是，DNA甲基化和组蛋白乙酰化的模式和水平在人类癌症中发生了深刻改变。越来越多的证据表明，一种表观遗传相互作用，即DNA甲基化和组蛋白乙酰化之间的相互作用，可能参与肿瘤中的基因转录和异常基因沉默过程。虽然基因激活的分子机制相对清楚，但在癌症发展过程中导致基因沉默的事件层次顺序和依赖性仍然很大程度上未知。一些研究表明，在基因沉默期间，DNA甲基化模式指导组蛋白修饰（包括组蛋白乙酰化和甲基化），而其他研究则认为DNA甲基化主要从组蛋白修饰状态获取线索。在这篇综述中，我们总结了目前关于基因沉默期间DNA甲基化和组蛋白修饰之间相互作用的知识，以及它在整合环境和内在刺激以控制基因表达方面的重要性。我们还讨论了表观遗传相互作用在抵御环境基因毒素引起的基因变化方面的重要性，以及对癌症治疗和预防的意义。
