Genome-wide depletion of replication initiation events in highly transcribed regions
Genome-wide depletion of replication initiation events in highly transcribed regions
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DOI：
10.1101/gr.124644.111
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发表时间：
2011-11-01
期刊：
影响因子：
7
通讯作者：
Aladjem, Mirit I.
中科院分区：
文献类型：
--
作者：
Martin, Melvenia M.;Ryan, Michael;Aladjem, Mirit I.
这份报告研究了哺乳动物细胞协调DNA复制与转录和染色质组装的机制。在酵母中，DNA复制在无核小体区域启动，但在哺乳动物细胞中的研究并未显示出类似的关系。在这里，我们使用全基因组大规模并行测序来定位复制起始事件，从而创建了两个人类细胞系中非重复DNA内所有复制起始点的数据库。挖掘这个数据库发现，在中等水平转录的基因组区域通常与高复制启动频率相关。在高转录速率的基因组区域，很少检测到复制起始事件。复制起始点的高分辨率作图表明，复制起始事件在转录起始点缺失，但在相邻的下游序列中高度浓缩。CpG序列的甲基化强烈影响复制起始事件的位置，而组蛋白修饰影响很小。这些观察表明，高水平的转录干扰复制前蛋白质复合体的形成。这里提供的数据确定了整个基因组中的复制起始点，为进一步分析DNA复制动力学和细胞周期进程提供了基础。
This report investigates the mechanisms by which mammalian cells coordinate DNA replication with transcription and chromatin assembly. In yeast, DNA replication initiates within nucleosome-free regions, but studies in mammalian cells have not revealed a similar relationship. Here, we have used genome-wide massively parallel sequencing to map replication initiation events, thereby creating a database of all replication initiation sites within nonrepetitive DNA in two human cell lines. Mining this database revealed that genomic regions transcribed at moderate levels were generally associated with high replication initiation frequency. In genomic regions with high rates of transcription, very few replication initiation events were detected. High-resolution mapping of replication initiation sites showed that replication initiation events were absent from transcription start sites but were highly enriched in adjacent, downstream sequences. Methylation of CpG sequences strongly affected the location of replication initiation events, whereas histone modifications had minimal effects. These observations suggest that high levels of transcription interfere with formation of pre-replication protein complexes. Data presented here identify replication initiation sites throughout the genome, providing a foundation for further analyses of DNA-replication dynamics and cell-cycle progression.