Weekley Benjamin H, Ahmed Newaz I, Maze Ian
Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
iScience. 2025 Feb 22;28(3):112092. doi: 10.1016/j.isci.2025.112092. eCollection 2025 Mar 21.
The evolving field of neuroepigenetics provides important insights into the molecular foundations of brain function. Novel sequencing technologies have identified patient-specific mutations and gene expression profiles involved in shaping the epigenetic landscape during neurodevelopment and in disease. Traditional methods to investigate the consequences of chromatin-related mutations provide valuable phenotypic insights but often lack information on the biochemical mechanisms underlying these processes. Recent studies, however, are beginning to elucidate how structural and/or functional aspects of histone, DNA, and RNA post-translational modifications affect transcriptional landscapes and neurological phenotypes. Here, we review the identification of epigenetic regulators from genomic studies of brain disease, as well as mechanistic findings that reveal the intricacies of neuronal chromatin regulation. We then discuss how these mechanistic studies serve as a guideline for future neuroepigenetics investigations. We end by proposing a roadmap to future therapies that exploit these findings by coupling them to recent advances in targeted therapeutics.
神经表观遗传学这一不断发展的领域为脑功能的分子基础提供了重要见解。新型测序技术已鉴定出在神经发育和疾病过程中塑造表观遗传格局所涉及的患者特异性突变和基因表达谱。研究染色质相关突变后果的传统方法提供了有价值的表型见解，但往往缺乏关于这些过程潜在生化机制的信息。然而，最近的研究开始阐明组蛋白、DNA和RNA翻译后修饰的结构和/或功能方面如何影响转录格局和神经表型。在这里，我们回顾了从脑部疾病基因组研究中鉴定表观遗传调节因子，以及揭示神经元染色质调节复杂性的机制性发现。然后，我们讨论这些机制性研究如何为未来的神经表观遗传学研究提供指导。我们最后提出了一条未来治疗的路线图，通过将这些发现与靶向治疗的最新进展相结合来加以利用。
