PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks.
PHD fingers in human diseases: disorders arising from misinterpreting epigenetic marks.
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DOI：
10.1016/j.mrfmmm.2008.07.004
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发表时间：
2008-12-01
影响因子：
2.3
通讯作者：
Wang, Gang G.
中科院分区：
文献类型：
--
作者：
Baker, Lindsey A.;Allis, C. David;Wang, Gang G.
组蛋白共价修饰调控许多（如果不是全部）DNA模板化过程，包括基因表达和DNA损伤反应。组蛋白修饰的生物学后果部分地由进化上保守的“阅读器/效应器”模块介导，所述模块以修饰和上下文特异性的方式结合组蛋白标记，随后产生染色质变化或招募其他蛋白质来这样做。最近，植物同源结构域（PHD）指已经作为一类专门的“阅读器”模块出现，其在某些情况下识别组蛋白赖氨酸残基的甲基化状态，例如组蛋白H3赖氨酸4（H3 K4）。而介导组蛋白修饰的添加或去除的催化酶中的突变（即，虽然已经知道修饰特异性“写入器”和“擦除器”）与各种人类疾病有关，但是修饰特异性“读取器”蛋白中的突变才开始被认为是导致人类疾病的原因。例如，靶向由许多基因（如RAG 2、ING、NSD 1和ATRX）编码的PHD指的点突变、缺失或染色体易位已经与广泛的人类病理学相关，包括免疫学病症、癌症和神经系统疾病。在这篇综述中，我们将讨论PHD手指的结构特征以及PHD手指直接突变或失调的疾病。我们认为，对表观遗传标记的误解可能是这类人类疾病的一般机制。确定组蛋白共价修饰在人类疾病背景下的调节作用将允许更彻底地理解正常和病理发展，并且可以提供创新的治疗策略，其中“染色质阅读器”作为潜在的药物靶点。
Histone covalent modifications regulate many, if not all, DNA-templated processes, including gene expression and DNA damage response. The biological consequences of histone modifications are mediated partially by evolutionarily conserved “reader/effector” modules that bind to histone marks in a modification- and context-specific fashion and subsequently enact chromatin changes or recruit other proteins to do so. Recently, the Plant Homeodomain (PHD) finger has emerged as a class of specialized “reader” modules that, in some instances, recognize the methylation status of histone lysine residues, such as histone H3 lysine 4 (H3K4). While mutations in catalytic enzymes that mediate the addition or removal of histone modifications (i.e., “writers” and “erasers”) are already known to be involved in various human diseases, mutations in the modification-specific “reader” proteins are only beginning to be recognized as contributing to human diseases. For instance, point mutations, deletions or chromosomal translocations that target PHD fingers encoded by many genes (such as RAG2, ING, NSD1 and ATRX) have been associated with a wide range of human pathologies including immunological disorders, cancers, and neurological diseases. In this review, we will discuss the structural features of PHD fingers as well as the diseases for which direct mutation or dysregulation of the PHD finger has been reported. We propose that misinterpretation of the epigenetic marks may serve as a general mechanism for human diseases of this category. Determining the regulatory roles of histone covalent modifications in the context of human disease will allow for a more thorough understanding of normal and pathological development, and may provide innovative therapeutic strategies wherein “chromatin readers” stand as potential drug targets.
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