The strand-biased mitochondrial DNA methylome and its regulation by DNMT3A
- Xiaoyang Dou1,2,8,
- Jerome D. Boyd-Kirkup1,8,
- Joseph McDermott1,8,
- Xiaoli Zhang1,3,8,
- Fang Li1,
- Bowen Rong4,
- Rui Zhang1,
- Bisi Miao4,
- Peilin Chen5,
- Hao Cheng1,
- Jianhuang Xue6,
- David Bennett7,
- Jiemin Wong5,
- Fei Lan4 and
- Jing-Dong J. Han1,3
- 1Key Laboratory of Computational Biology, CAS Center for Excellence in Molecular Cell Science, Collaborative Innovation Center for Genetics and Developmental Biology, Chinese Academy of Sciences–Max Planck Partner Institute for Computational Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China;
- 2University of Chinese Academy of Sciences, Beijing 100049, China;
- 3Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Center for Quantitative Biology (CQB), Peking University, Beijing 100871, China;
- 4Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Key Laboratory of Epigenetics, Shanghai Ministry of Education, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China;
- 5Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China;
- 6The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China;
- 7Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois 60612, USA
Abstract
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.
Footnotes
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↵8 Co-first author.
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.234021.117.
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Freely available online through the Genome Research Open Access option.
- Received January 18, 2019.
- Accepted August 23, 2019.
This article, published in Genome Research, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.
