H2A.Z facilitates licensing and activation of early replication origins
H2A.Z facilitates licensing and activation of early replication origins
复制标题
H2A.Z 促进早期复制起点的许可和激活
DOI：
10.1038/s41586-019-1877-9
复制
发表时间：
2019-12-25
期刊：
影响因子：
64.8
通讯作者：
Li, Guohong
中科院分区：
文献类型：
--
作者：
Long, Haizhen;Zhang, Liwei;Li, Guohong
DNA复制是一个严格调控的过程，确保了细胞周期中基因组的精确复制。在真核生物中，复制起点的许可和激活受到DNA序列和染色质特征的调节2。然而，基于染色质的调节机制仍然在很大程度上未被表征。在这里，我们表明，在HeLa细胞中，核小体含有组蛋白变体H2A.Z富含组蛋白H4，其赖氨酸20残基（H4 K20 me 2）和结合的起源识别复合物（ORC）被二甲基化。体外研究表明，含H2 A. Z的核小体直接与组蛋白赖氨酸甲基转移酶SUV 420 H1结合，促进H4 K20 me 2沉积，这反过来又是ORC 1结合所需的。全基因组研究表明，来自H4 K20 me 2、ORC 1和新生DNA链的信号与H2A.Z共定位，并且H2A.Z的缺失导致整个基因组中H4 K20 me 2、ORC 1和新生链信号的减少。H2 A.与其他复制起点相比，Z调控的复制起点具有更高的点火效率和更早的复制时间。我们的研究结果表明，组蛋白变体H2A.Z表观遗传调节许可和激活早期复制起点，并通过SUV 420 H1-H4 K20 me 2-ORC 1轴维持复制时间。
DNA replication is a tightly regulated process that ensures the precise duplication of the genome during the cell cycle1. In eukaryotes, the licensing and activation of replication origins are regulated by both DNA sequence and chromatin features2. However, the chromatin-based regulatory mechanisms remain largely uncharacterized. Here we show that, in HeLa cells, nucleosomes containing the histone variant H2A.Z are enriched with histone H4 that is dimethylated on its lysine 20 residue (H4K20me2) and with bound origin-recognition complex (ORC). In vitro studies show that H2A.Z-containing nucleosomes bind directly to the histone lysine methyltransferase enzyme SUV420H1, promoting H4K20me2 deposition, which is in turn required for ORC1 binding. Genome-wide studies show that signals from H4K20me2, ORC1 and nascent DNA strands co-localize with H2A.Z, and that depletion of H2A.Z results in decreased H4K20me2, ORC1 and nascent-strand signals throughout the genome. H2A.Z-regulated replication origins have a higher firing efficiency and early replication timing compared with other origins. Our results suggest that the histone variant H2A.Z epigenetically regulates the licensing and activation of early replication origins and maintains replication timing through the SUV420H1-H4K20me2-ORC1 axis.