G9a Plays Distinct Roles in Maintaining DNA Methylation, Retrotransposon Silencing, and Chromatin Looping
G9a Plays Distinct Roles in Maintaining DNA Methylation, Retrotransposon Silencing, and Chromatin Looping
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DOI：
10.1016/j.celrep.2020.108315
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发表时间：
2020-10-27
期刊：
影响因子：
8.8
通讯作者：
Leung, Danny C. Y.
中科院分区：
文献类型：
--
作者：
Jiang, Qinghong;Ang, Julie Y. J.;Leung, Danny C. Y.
G9a是一种调节表观遗传修饰、转录和基因组组织的赖氨酸甲基转移酶。然而，这些性质是相互依赖还是代表G9a的不同功能尚不清楚。在这项研究中，我们观察到在G9a缺失和催化突变的胚胎干细胞中广泛存在DNA甲基化缺失。此外，我们定义了G9a如何以催化依赖和独立的方式调节染色质可及性、表观遗传修饰和转录沉默。重新激活的反转录转座子提供了替代的启动子和剪接位点，导致邻近基因的上调和嵌合转录物的产生。此外，虽然拓扑结构域和室A/B定义在很大程度上不受影响，但G9a的缺失会导致染色质状态改变，CTCF和内聚蛋白结合异常，以及染色质环的差异，尤其是在反转录转座子上。综上所述，我们的发现揭示了G9a如何以不同的机制调节表观基因组、转录组和高阶染色质结构。
G9a is a lysine methyltransferase that regulates epigenetic modifications, transcription, and genome organization. However, whether these properties are dependent on one another or represent distinct functions of G9a remains unclear. In this study, we observe widespread DNA methylation loss in G9a depleted and catalytic mutant embryonic stem cells. Furthermore, we define how G9a regulates chromatin accessibility, epigenetic modifications, and transcriptional silencing in both catalytic-dependent and -independent manners. Reactivated retrotransposons provide alternative promoters and splice sites leading to the upregulation of neighboring genes and the production of chimeric transcripts. Moreover, while topologically associated domains and compartment A/B definitions are largely unaffected, the loss of G9a leads to altered chromatin states, aberrant CTCF and cohesin binding, and differential chromatin looping, especially at retrotransposons. Taken together, our findings reveal how G9a regulates the epigenome, transcriptome, and higher-order chromatin structures in distinct mechanisms.