The strand-biased mitochondrial DNA methylome and its regulation by DNMT3A
The strand-biased mitochondrial DNA methylome and its regulation by DNMT3A
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链偏向线粒体 DNA 甲基化及其 DNMT3A 的调控
DOI：
10.1101/gr.234021.117
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发表时间：
2019-10-01
期刊：
影响因子：
7
通讯作者：
Han, Jing-Dong J.
中科院分区：
文献类型：
--
作者：
Dou, Xiaoyang;Boyd-Kirkup, Jerome D.;Han, Jing-Dong J.
单个基因是如何从线粒体多顺反子转录物调节到具有可变表达的仍然是一个谜。在这里，通过亚硫酸氢盐测序和链特异性作图，我们显示人类和其他动物的线粒体基因组强烈偏向于轻（L）链非CpG甲基化，保守的峰位点优先位于基因-基因边界，这也通过MeDIP和FspEI消化独立验证。这种mtDNA甲基化模式在不同的物种和发育阶段是保守的，但在发育和衰老过程中显示动态的局部或全局变化。单独敲除DNMT 3A会扰乱mtDNA区域甲基化模式，但不会影响整体水平，并改变线粒体基因表达、拷贝数和氧呼吸。DNMT 3A的过表达强烈增加mtDNA甲基化和链偏性。总的来说，基因体和边界的甲基化与线粒体转录本丰度和多顺反子转录本加工呈负相关。此外，HPLC-MS证实了线粒体DNA上的甲基化信号。总之，这些数据提供了高分辨率的mtDNA甲基化图谱，揭示了链特异性非CpG甲基化，其动态调节及其对多顺反子线粒体转录物加工的影响。
How individual genes are regulated from a mitochondrial polycistronic transcript to have variable expression remains an enigma. Here, through bisulfite sequencing and strand-specific mapping, we show mitochondrial genomes in humans and other animals are strongly biased to light (L)-strand non-CpG methylation with conserved peak loci preferentially located at gene–gene boundaries, which was also independently validated by MeDIP and FspEI digestion. Such mtDNA methylation patterns are conserved across different species and developmental stages but display dynamic local or global changes during development and aging. Knockout of DNMT3A alone perturbed mtDNA regional methylation patterns, but not global levels, and altered mitochondrial gene expression, copy number, and oxygen respiration. Overexpression of DNMT3A strongly increased mtDNA methylation and strand bias. Overall, methylation at gene bodies and boundaries was negatively associated with mitochondrial transcript abundance and also polycistronic transcript processing. Furthermore, HPLC-MS confirmed the methylation signals on mitochondria DNA. Together, these data provide high-resolution mtDNA methylation maps that revealed a strand-specific non-CpG methylation, its dynamic regulation, and its impact on the polycistronic mitochondrial transcript processing.