Histone deacetylases (HDACs) are a family of enzymes that deacetylate histones as well as a large number of other nuclear, cytoplasmic, and mitochondrial proteins. The deacetylation of histones transforms chromatin to a transcriptionally repressed state, whereas deacetylation of other cellular proteins regulates their functional activity through modulation of subcellular location, their interaction with other proteins, and in the case of transcription factors, their DNA-binding ability. A compelling body of evidence derived from the utilization of pharmacological inhibitors indicates that histone deacetylases are important regulators of brain development as well as the pathogenesis of neurodegenerative diseases. However, because most of the pharmacological inhibitors used are non-selective with regard to the different members of the HDAC family, the significance of individual HDAC proteins to brain development and degeneration has been difficult to delineate. This review focuses on HDAC3. Experiments conducted using more recently developed isoform selective inhibitors and molecular genetic approaches demonstrate that HDAC3 regulates different steps of neurodevelopment, including neurogenesis, gliogenesis, glial cell fate determination, and the myelination of oligodendrocytes and Schwann cells. However, specific posttranslational modifications and alterations in its binding partners transform HDAC3 from a protein that is beneficial to the brain to one that is neurotoxic. The role of HDAC3 in the promotion of neurodegeneration and the inhibition of recovery after nerve injury is reviewed. The role of HDAC3 in the regulation of memory in the adult and aging brain is also described.

Impact statement

Brain development and degeneration are highly complex processes that are regulated by a large number of molecules and signaling pathways the identities of which are being unraveled. Accumulating evidence points to histone deacetylases and epigenetic mechanisms as being important regulators of these processes. In this review, we describe that histone deacetylase-3 (HDAC3) is a particularly crucial regulator of both neurodevelopment and neurodegeneration. In addition, HDAC3 regulates memory formation, synaptic plasticity, and the cognitive impairment associated with normal aging. Understanding how HDAC3 functions contributes to the normal development and functioning of the brain while also promoting neurodegeneration could lead to the development of therapeutic approaches for neurodevelopmental, neuropsychiatric, and neurodegenerative disorders.

中文翻译：

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组蛋白脱乙酰酶 3：大脑的朋友和敌人。

组蛋白脱乙酰酶 (HDAC) 是一个酶家族，可对组蛋白以及大量其他核蛋白、细胞质蛋白和线粒体蛋白进行脱乙酰化。组蛋白的脱乙酰化将染色质转变为转录抑制状态，而其他细胞蛋白质的脱乙酰化则通过调节亚细胞位置、它们与其他蛋白质的相互作用以及转录因子的 DNA 结合能力来调节其功能活性。来自药物抑制剂的使用的大量令人信服的证据表明，组蛋白脱乙酰酶是大脑发育以及神经退行性疾病发病机制的重要调节因子。然而，由于大多数使用的药物抑制剂对于 HDAC 家族的不同成员都是非选择性的，因此很难描述单个 HDAC 蛋白对大脑发育和退化的重要性。本综述重点关注 HDAC3。使用最近开发的异构体选择性抑制剂和分子遗传学方法进行的实验表明，HDAC3 调节神经发育的不同步骤，包括神经发生、胶质细胞生成、神经胶质细胞命运决定以及少突胶质细胞和雪旺细胞的髓鞘形成。然而，其结合伙伴的特定翻译后修饰和改变将 HDAC3 从一种对大脑有益的蛋白质转变为一种具有神经毒性的蛋白质。综述了 HDAC3 在促进神经退行性变和抑制神经损伤后恢复中的作用。还描述了 HDAC3 在成人和衰老大脑记忆调节中的作用。

影响报告

大脑发育和退化是高度复杂的过程，受到大量分子和信号通路的调节，这些分子和信号通路的特性正在被揭开。越来越多的证据表明组蛋白脱乙酰酶和表观遗传机制是这些过程的重要调节因子。在这篇综述中，我们描述了组蛋白脱乙酰酶 3 (HDAC3) 是神经发育和神经变性的一个特别重要的调节因子。此外，HDAC3 还调节记忆形成、突触可塑性以及与正常衰老相关的认知障碍。了解 HDAC3 的功能如何促进大脑的正常发育和功能，同时促进神经退行性变，可能有助于开发神经发育、神经精神和神经退行性疾病的治疗方法。