Abnormalities of the DNA methylation mark and its machinery: an emerging cause of neurologic dysfunction.
Abnormalities of the DNA methylation mark and its machinery: an emerging cause of neurologic dysfunction.
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DNA 甲基化标记及其机制的异常：神经功能障碍的新原因。
DOI：
10.1055/s-0034-1386763
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发表时间：
2014
影响因子：
2.7
通讯作者：
Bjornsson,HansT
中科院分区：
文献类型：
--
作者：
Weissman,Jacqueline;Naidu,Sakkubai;Bjornsson,HansT
最近，已经描述了DNA甲基化机制的孟德尔疾病，其证明了表观遗传学在神经发育和疾病中的复杂作用。例如，DNMT1（维持甲基转移酶）的缺陷导致成人发作的进行性神经系统疾病，而从头甲基转移酶DNMT3A和DNMT3B的缺陷导致非进行性神经发育状况。此外，DNMT3A缺乏症患者表现出过度生长，这是组蛋白机制障碍和印记障碍的共同特征，突出了许多表观遗传层的相互联系。DNA甲基化机制的障碍包括上述甲基标记的“写入者”和“读取者”，例如导致Rett综合征的MeCP 2。任何剂量中断，DNA甲基化机制的单倍不足或过表达都会导致广泛的反式基因表达变化，破坏有助于个体疾病表型的靶基因子集的表达。与此相反，经典的印迹疾病，如安格尔曼综合征已被认为是普遍引起表观遗传失调切口。然而，最近描述的多位点甲基化障碍的挑战这一概括。在这里，除了总结在确定这些疾病的发病机制的最新进展，我们强调的临床考虑和一些意想不到的治疗机会，如拓扑异构酶抑制剂的经典印迹疾病。
Recently, Mendelian disorders of the DNA methylation machinery have been described which demonstrate the complex roles of epigenetics in neurodevelopment and disease. For example, defects of DNMT1, the maintenance methyltransferase, lead to adult-onset progressive neurologic disorders, whereas defects of the de novo methyltransferases DNMT3A and DNMT3B lead to nonprogressive neurodevelopmental conditions. Furthermore, patients with DNMT3A deficiency demonstrate overgrowth, a feature common to disorders of histone machinery and imprinting disorders, highlighting the interconnectedness of the many epigenetic layers. Disorders of the DNA methylation machinery include both the aforementioned “writers” and also the “readers” of the methyl mark, such as MeCP2, the cause of Rett syndrome. Any dosage disruption, either haploinsufficiency or overexpression of DNA methylation machinery leads to widespread gene expression changes intrans, disrupting expression of a subset of target genes that contribute to individual disease phenotypes. In contrast, classical imprinting disorders such as Angelman syndrome have been thought generally to cause epigenetic dysregulation incis. However, the recent description of multilocus methylation disorders challenges this generalization. Here, in addition to summarizing recent developments in identifying the pathogenesis of these diseases, we highlight clinical considerations and some unexpected therapeutic opportunities, such as topoisomerase inhibitors for classical imprinting disorders.