Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Biochemistry and Molecular Biophysics, University of Washington School of Medicine, St. Louis, MO, USA.
Crit Rev Biochem Mol Biol. 2022 Feb;57(1):73-112. doi: 10.1080/10409238.2021.1979457. Epub 2021 Oct 2.
The etiology of neurodevelopmental disorders (NDDs) remains a challenge for researchers. Human brain development is tightly regulated and sensitive to cellular alterations caused by endogenous or exogenous factors. Intriguingly, the surge of clinical sequencing studies has revealed that many of these disorders are monogenic and monoallelic. Notably, chromatin regulation has emerged as highly dysregulated in NDDs, with many syndromes demonstrating phenotypic overlap, such as intellectual disabilities, with one another. Here we discuss epigenetic writers, erasers, readers, remodelers, and even histones mutated in NDD patients, predicted to affect gene regulation. Moreover, this review focuses on disorders associated with mutations in enzymes involved in histone acetylation and methylation, and it highlights syndromes involving chromatin remodeling complexes. Finally, we explore recently discovered histone germline mutations and their pathogenic outcome on neurological function. Epigenetic regulators are mutated at every level of chromatin organization. Throughout this review, we discuss mechanistic investigations, as well as various animal and iPSC models of these disorders and their usefulness in determining pathomechanism and potential therapeutics. Understanding the mechanism of these mutations will illuminate common pathways between disorders. Ultimately, classifying these disorders based on their effects on the epigenome will not only aid in prognosis in patients but will aid in understanding the role of epigenetic machinery throughout neurodevelopment.
神经发育障碍 (NDD) 的病因仍然是研究人员面临的挑战。人类大脑的发育受到严格的调控，容易受到内源性或外源性因素引起的细胞变化的影响。有趣的是，大量临床测序研究表明，许多这些疾病是单基因和单等位基因的。值得注意的是，染色质调控在 NDD 中高度失调，许多综合征彼此之间表现出表型重叠，例如智力障碍。在这里，我们讨论了在 NDD 患者中预测会影响基因调控的表观遗传写入器、擦除器、读取器、重塑器，甚至是突变的组蛋白。此外，本综述重点介绍了与涉及组蛋白乙酰化和甲基化的酶的突变相关的疾病，并强调了涉及染色质重塑复合物的综合征。最后，我们探讨了最近发现的组蛋白种系突变及其对神经功能的致病后果。表观遗传调节剂在染色质组织的各个层面都发生突变。在整篇综述中，我们讨论了机制研究，以及这些疾病的各种动物和 iPSC 模型及其在确定病理机制和潜在治疗方法方面的用途。了解这些突变的机制将阐明疾病之间的共同途径。最终，基于它们对表观基因组的影响对这些疾病进行分类，不仅将有助于患者的预后，还有助于了解表观遗传机制在神经发育过程中的作用。
