MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs.
MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs.
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DOI：
10.1016/j.celrep.2016.08.087
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发表时间：
2016-09-27
期刊：
影响因子：
8.8
通讯作者：
Reik W
中科院分区：
文献类型：
--
作者：
Eckersley-Maslin MA;Svensson V;Krueger C;Stubbs TM;Giehr P;Krueger F;Miragaia RJ;Kyriakopoulos C;Berrens RV;Milagre I;Walter J;Teichmann SA;Reik W
小鼠胚胎干细胞是动态的和异质性的。例如，罕见的细胞经历一种以染色质解缩和转录本表达为特征的状态，包括Zscan4簇和MERVL内源性逆转录病毒，这通常仅限于植入前胚胎。在这里，我们进一步描述了这种瞬时细胞状态的动力学和后果。单细胞转录组学鉴定了细胞进入MERVL/Zscan4状态时最早上调的转录本。在诱导多能干细胞重编程过程中，MERVL/Zscan4转录网络也上调。全基因组DNA甲基化和染色质分析显示，全球DNA低甲基化伴随着染色质可及性的增加。这种短暂的DNA去甲基化是由细胞中DNA甲基转移酶蛋白的丢失驱动的，并发生在整个基因组中。虽然一旦细胞退出这种状态，甲基化水平就会恢复，但基因组印记仍然处于低甲基化状态，这表明内源性逆转录病毒激活对表观基因组具有潜在的全球和持久的影响。单细胞转录组学显示MERVL/Zscan4网络激活的动力学MERVL-LTR转录网络表达在IPSC重编程事件中，翻译阻断耗尽Dnmt蛋白，诱导瞬时的全局去甲基化通路通过MERVL/Zscan4状态可能导致不可逆转的印迹擦除小鼠胚胎干细胞零星表达着床前转录产物，包括MERVL内源性逆转录病毒和Zscan4簇。埃克斯利-马斯林等人。研究这些细胞的转录动态，揭示伴随着染色质解压的短暂的全基因组DNA去甲基化。在国家退出后，甲基化水平恢复，除了基因组印记，它仍然丢失。
Mouse embryonic stem cells are dynamic and heterogeneous. For example, rare cells cycle through a state characterized by decondensed chromatin and expression of transcripts, including the Zscan4 cluster and MERVL endogenous retrovirus, which are usually restricted to preimplantation embryos. Here, we further characterize the dynamics and consequences of this transient cell state. Single-cell transcriptomics identified the earliest upregulated transcripts as cells enter the MERVL/Zscan4 state. The MERVL/Zscan4 transcriptional network was also upregulated during induced pluripotent stem cell reprogramming. Genome-wide DNA methylation and chromatin analyses revealed global DNA hypomethylation accompanying increased chromatin accessibility. This transient DNA demethylation was driven by a loss of DNA methyltransferase proteins in the cells and occurred genome-wide. While methylation levels were restored once cells exit this state, genomic imprints remained hypomethylated, demonstrating a potential global and enduring influence of endogenous retroviral activation on the epigenome. Single-cell transcriptomics reveals dynamics of MERVL/Zscan4 network activation MERVL-LTR transcriptional network is expressed in iPSC reprogramming events Translation block depletes Dnmt proteins, inducing transient global demethylation Passage through the MERVL/Zscan4 state may cause irreversible imprint erasure Mouse embryonic stem cells sporadically express preimplantation transcripts, including the MERVL endogenous retrovirus and Zscan4 cluster. Eckersley-Maslin et al. investigate the transcriptional dynamics in these cells and reveal transient genome-wide DNA demethylation accompanying chromatin decompaction. Following state exit, methylation levels are restored, except for genomic imprints, which remain lost.
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16.8
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