Baker Lindsey A, Allis C David, Wang Gang G
The Rockefeller University, Laboratory of Chromatin Biology & Epigenetics, New York, NY 10065, USA.
Mutat Res. 2008 Dec 1;647(1-2):3-12. doi: 10.1016/j.mrfmmm.2008.07.004. Epub 2008 Jul 17.
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 recombination activating gene 2 (RAG2), Inhibitor of Growth (ING), nuclear receptor-binding SET domain-containing 1 (NSD1) and Alpha Thalassaemia and Mental Retardation Syndrome, X-linked (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.
组蛋白共价修饰调控着许多（即便不是所有）以DNA为模板的过程，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是由进化上保守的“读取器/效应器”模块介导的，这些模块以修饰和上下文特异性的方式与组蛋白标记结合，随后引发染色质变化或招募其他蛋白质来实现这一目的。最近，植物同源结构域（PHD）指已成为一类特殊的“读取器”模块，在某些情况下，它们能够识别组蛋白赖氨酸残基的甲基化状态，比如组蛋白H3赖氨酸4（H3K4）。虽然已知介导组蛋白修饰添加或去除的催化酶（即“书写者”和“擦除者”）中的突变与多种人类疾病有关，但修饰特异性“读取器”蛋白中的突变才刚刚开始被认为与人类疾病有关。例如，针对许多基因编码的PHD指的点突变、缺失或染色体易位（如重组激活基因2（RAG2）、生长抑制因子（ING）、含核受体结合SET结构域1（NSD1）以及X连锁的α地中海贫血和智力发育迟缓综合征（ATRX））已与广泛的人类病理状况相关，包括免疫紊乱、癌症和神经疾病。在本综述中，我们将讨论PHD指的结构特征以及已报道PHD指直接突变或失调与之相关的疾病。我们提出，表观遗传标记的错误解读可能是这类人类疾病的一种普遍机制。确定组蛋白共价修饰在人类疾病背景下的调控作用将有助于更全面地理解正常和病理发育过程，并可能提供创新的治疗策略，其中“染色质读取器”可作为潜在的药物靶点。
