Université de Paris, Epigénétique et Destin Cellulaire, CNRS, Paris F-75013, France.
Aix Marseille Univ, INSERM, MMG, Marseille Medical Genetics, Marseille, France.
Essays Biochem. 2019 Dec 20;63(6):757-771. doi: 10.1042/EBC20190028.
Despite the tremendous progress made in recent years in assembling the human genome, tandemly repeated DNA elements remain poorly characterized. These sequences account for the vast majority of methylated sites in the human genome and their methylated state is necessary for this repetitive DNA to function properly and to maintain genome integrity. Furthermore, recent advances highlight the emerging role of these sequences in regulating the functions of the human genome and its variability during evolution, among individuals, or in disease susceptibility. In addition, a number of inherited rare diseases are directly linked to the alteration of some of these repetitive DNA sequences, either through changes in the organization or size of the tandem repeat arrays or through mutations in genes encoding chromatin modifiers involved in the epigenetic regulation of these elements. Although largely overlooked so far in the functional annotation of the human genome, satellite elements play key roles in its architectural and topological organization. This includes functions as boundary elements delimitating functional domains or assembly of repressive nuclear compartments, with local or distal impact on gene expression. Thus, the consideration of satellite repeats organization and their associated epigenetic landmarks, including DNA methylation (DNAme), will become unavoidable in the near future to fully decipher human phenotypes and associated diseases.
尽管近年来在组装人类基因组方面取得了巨大进展，但串联重复 DNA 元件的特征仍描述不足。这些序列占人类基因组中绝大多数甲基化位点，其甲基化状态对于这些重复 DNA 正常发挥功能和维持基因组完整性是必要的。此外，最近的进展强调了这些序列在调节人类基因组功能及其在进化、个体间或疾病易感性中的变异性方面的新兴作用。此外，许多遗传性罕见疾病直接与一些重复 DNA 序列的改变有关，这些改变要么是通过串联重复阵列的组织或大小的改变，要么是通过参与这些元件表观遗传调控的染色质修饰基因的突变。尽管在人类基因组的功能注释中迄今为止在很大程度上被忽视，但卫星元件在其结构和拓扑组织中起着关键作用。这包括作为功能域边界元件或抑制性核区室组装的功能，对基因表达具有局部或远端影响。因此，在不久的将来，卫星重复序列的组织及其相关的表观遗传标记，包括 DNA 甲基化（DNAme），将不可避免地用于全面破译人类表型及其相关疾病。
