Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.
Mol Neurobiol. 2023 Feb;60(2):768-779. doi: 10.1007/s12035-022-03106-9. Epub 2022 Nov 11.
How DNA is folded and packaged in nucleosomes is an essential regulator of gene expression. Abnormal patterns of chromatin folding are implicated in a wide range of diseases and disorders, including epilepsy and autism spectrum disorder (ASD). These disorders are thought to have a shared pathogenesis involving an imbalance in the number of excitatory-inhibitory neurons formed during neurodevelopment; however, the underlying pathological mechanism behind this imbalance is poorly understood. Studies are increasingly implicating abnormal chromatin folding in neural stem cells as one of the candidate pathological mechanisms, but no review has yet attempted to summarise the knowledge in this field. This meta-synthesis is a systematic search of all the articles on epilepsy, ASD, and chromatin folding. Its two main objectives were to determine to what extent abnormal chromatin folding is implicated in the pathogenesis of epilepsy and ASD, and secondly how abnormal chromatin folding leads to pathological disease processes. This search produced 22 relevant articles, which together strongly implicate abnormal chromatin folding in the pathogenesis of epilepsy and ASD. A range of mutations and chromosomal structural abnormalities lead to this effect, including single nucleotide polymorphisms, copy number variants, translocations and mutations in chromatin modifying. However, knowledge is much more limited into how abnormal chromatin organisation subsequently causes pathological disease processes, not yet showing, for example, whether it leads to abnormal excitation-inhibitory neuron imbalance in human brain organoids.
DNA 如何在核小体中折叠和包装是基因表达的重要调节剂。染色质折叠的异常模式与广泛的疾病和紊乱有关，包括癫痫和自闭症谱系障碍 (ASD)。这些疾病被认为具有共同的发病机制，涉及神经发育过程中兴奋性神经元和抑制性神经元形成数量的失衡；然而，这种失衡背后的潜在病理机制尚不清楚。越来越多的研究表明，神经干细胞中的异常染色质折叠是候选病理机制之一，但尚未有综述试图总结该领域的知识。本荟萃分析是对所有关于癫痫、ASD 和染色质折叠的文章进行的系统搜索。其两个主要目的是确定异常染色质折叠在癫痫和 ASD 发病机制中的程度，其次是异常染色质折叠如何导致病理疾病过程。这项搜索产生了 22 篇相关文章，它们强烈表明异常染色质折叠与癫痫和 ASD 的发病机制有关。一系列突变和染色体结构异常导致了这种效应，包括单核苷酸多态性、拷贝数变异、易位和染色质修饰的突变。然而，对于异常染色质组织如何随后导致病理疾病过程，我们的了解要有限得多，例如，它是否会导致人类脑类器官中异常的兴奋-抑制神经元失衡，目前尚未有研究表明。
