Tchurikov Nickolai A, Fedoseeva Daria M, Sosin Dmitri V, Snezhkina Anastasia V, Melnikova Nataliya V, Kudryavtseva Anna V, Kravatsky Yuri V, Kretova Olga V
Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia
Department of Epigenetic Mechanisms of Gene Expression Regulation, Engelhardt Institute of Molecular Biology, Moscow 119334, Russia.
J Mol Cell Biol. 2015 Aug;7(4):366-82. doi: 10.1093/jmcb/mju038. Epub 2014 Oct 3.
DNA double-strand breaks (DSBs) are involved in many cellular mechanisms, including replication, transcription, and genome rearrangements. The recent observation that hot spots of DSBs in human chromosomes delimit DNA domains that possess coordinately expressed genes suggests a strong relationship between the organization of transcription patterns and hot spots of DSBs. In this study, we performed mapping of hot spots of DSBs in a human 43-kb ribosomal DNA (rDNA) repeated unit. We observed that rDNA units corresponded to the most fragile sites in human chromosomes and that these units possessed at least nine specific regions containing clusters of extremely frequently occurring DSBs, which were located exclusively in non-coding intergenic spacer (IGS) regions. The hot spots of DSBs corresponded to only a specific subset of DNase-hypersensitive sites, and coincided with CTCF, PARP1, and HNRNPA2B1 binding sites, and H3K4me3 marks. Our rDNA-4C data indicate that the regions of IGS containing the hot spots of DSBs often form contacts with specific regions in different chromosomes, including the pericentromeric regions, as well as regions that are characterized by H3K27ac and H3K4me3 marks, CTCF binding sites, ChIA-PET and RIP signals, and high levels of DSBs. The data suggest a strong link between chromosome breakage and several different mechanisms of epigenetic regulation of gene expression.
DNA双链断裂（DSB）参与多种细胞机制，包括复制、转录和基因组重排。最近观察到人类染色体中DSB的热点界定了具有协同表达基因的DNA结构域，这表明转录模式的组织与DSB热点之间存在密切关系。在本研究中，我们对人类43kb核糖体DNA（rDNA）重复单元中的DSB热点进行了定位。我们观察到rDNA单元对应于人类染色体中最脆弱的位点，并且这些单元拥有至少九个特定区域，其中包含极其频繁出现的DSB簇，这些区域仅位于非编码基因间隔区（IGS）。DSB热点仅对应于特定子集的DNase超敏位点，并且与CTCF、PARP1和HNRNPA2B1结合位点以及H3K4me3标记重合。我们的rDNA-4C数据表明，包含DSB热点的IGS区域通常与不同染色体中的特定区域形成接触，包括着丝粒周围区域，以及以H3K27ac和H3K4me3标记、CTCF结合位点、ChIA-PET和RIP信号以及高水平DSB为特征的区域。这些数据表明染色体断裂与基因表达的几种不同表观遗传调控机制之间存在强大联系。
