Department of Psychiatry, University of Illinois, Chicago, IL 60612, USA.
Mol Pharmacol. 2010 Feb;77(2):126-35. doi: 10.1124/mol.109.061333. Epub 2009 Nov 16.
In recent years, it has become widely recognized that a comprehensive understanding of chromatin biology is necessary to better appreciate its role in a wide range of diseases. The histone code has developed as a new layer of our appreciation of transcription factor-based mechanisms of gene expression. Although epigenetic regulation refers to a host of chromatin modifications that occur at the level of DNA, histones, and histone-associated proteins, how this regulation is orchestrated is still incompletely understood. Of those processes that comprise the epigenetic regulatory machinery, DNA methylation and histone acetylation/deacetylation have been the most thoroughly studied. Compounds that act as inhibitors of DNA methyltransferases or histone deacetylases (HDACs) activate a variety of intracellular signaling pathways that ultimately affect the coordinated expression of multiple genes. The altered patterns of mRNA and protein expression collectively converge on pathways linked to apoptosis and cell cycle arrest, among others. This has prompted a widespread search for epigenetic inhibitors that could be used as chemotherapeutic agents, and several are undergoing clinical evaluation. More recently, there has been interest in the use of HDAC inhibitors to activate the expression of mRNAs that are down-regulated in various neurological and psychiatric conditions. Considerably less is known regarding the effect these drugs have on postmitotic cells such as neurons. Before we consider the clinical use of additional HDAC inhibitors to treat schizophrenia or unipolar depression, there are a number of key issues that need to be resolved.
近年来，人们越来越认识到，要全面了解染色质生物学，就有必要更好地理解其在广泛的疾病中的作用。组蛋白密码的发展是我们对基于转录因子的基因表达机制的理解的新层次。尽管表观遗传调控是指在 DNA、组蛋白和组蛋白相关蛋白水平上发生的一系列染色质修饰，但这种调控是如何协调的仍不完全清楚。在构成表观遗传调控机制的那些过程中，DNA 甲基化和组蛋白乙酰化/去乙酰化研究得最为透彻。作为 DNA 甲基转移酶或组蛋白去乙酰化酶 (HDAC) 抑制剂的化合物激活了多种细胞内信号通路，最终影响多个基因的协调表达。mRNA 和蛋白质表达的改变模式共同集中在与细胞凋亡和细胞周期停滞等相关的途径上。这促使人们广泛寻找可作为化疗药物的表观遗传抑制剂，其中一些正在进行临床评估。最近，人们对使用 HDAC 抑制剂来激活各种神经和精神疾病中下调的 mRNA 的表达产生了兴趣。关于这些药物对有丝分裂后细胞（如神经元）的影响，人们了解得要少得多。在我们考虑使用额外的 HDAC 抑制剂来治疗精神分裂症或单相抑郁症之前，有许多关键问题需要解决。
