Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.
Nat Rev Drug Discov. 2012 Apr 13;11(5):384-400. doi: 10.1038/nrd3674.
Epigenetic regulation of gene expression is a dynamic and reversible process that establishes normal cellular phenotypes but also contributes to human diseases. At the molecular level, epigenetic regulation involves hierarchical covalent modification of DNA and the proteins that package DNA, such as histones. Here, we review the key protein families that mediate epigenetic signalling through the acetylation and methylation of histones, including histone deacetylases, protein methyltransferases, lysine demethylases, bromodomain-containing proteins and proteins that bind to methylated histones. These protein families are emerging as druggable classes of enzymes and druggable classes of protein-protein interaction domains. In this article, we discuss the known links with disease, basic molecular mechanisms of action and recent progress in the pharmacological modulation of each class of proteins.
基因表达的表观遗传调控是一个动态且可逆的过程，它不仅建立了正常的细胞表型，也与人类疾病有关。在分子水平上，表观遗传调控涉及 DNA 和包装 DNA 的蛋白质（如组蛋白）的分层共价修饰。在这里，我们综述了通过组蛋白乙酰化和甲基化来介导表观遗传信号的关键蛋白家族，包括组蛋白去乙酰化酶、蛋白甲基转移酶、赖氨酸去甲基酶、含有溴结构域的蛋白以及与甲基化组蛋白结合的蛋白。这些蛋白家族正在成为可药物化的酶类和可药物化的蛋白-蛋白相互作用结构域类。在本文中，我们讨论了与疾病的已知联系、作用的基本分子机制以及每种蛋白的药理学调节的最新进展。
