The dynamics of DNA methylation fidelity during mouse embryonic stem cell self-renewal and differentiation
- Lei Zhao1,6,
- Ming-an Sun2,6,
- Zejuan Li3,6,
- Xue Bai1,
- Miao Yu4,
- Min Wang2,
- Liji Liang1,
- Xiaojian Shao1,
- Stephen Arnovitz3,
- Qianfei Wang1,
- Chuan He4,
- Xuemei Lu1,
- Jianjun Chen3 and
- Hehuang Xie1,2,5
- 1Laboratory of Genome Variation and Precision Biomedicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
- 2Epigenomics and Computational Biology Lab, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia 24060, USA;
- 3Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA;
- 4Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA;
- 5Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24060, USA
- Corresponding authors: davidxie{at}vt.edu, chen{at}bsd.uchicago.edu, luxm{at}big.ac.cn
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↵6 These authors contributed equally to this work.
Abstract
The faithful transmission of DNA methylation patterns through cell divisions is essential for the daughter cells to retain a proper cell identity. To achieve a comprehensive assessment of methylation fidelity, we implemented a genome-scale hairpin bisulfite sequencing approach to generate methylation data for DNA double strands simultaneously. We show here that methylation fidelity increases globally during differentiation of mouse embryonic stem cells (mESCs), and is particularly high in the promoter regions of actively expressed genes and positively correlated with active histone modification marks and binding of transcription factors. The majority of intermediately (40%–60%) methylated CpG dinucleotides are hemi-methylated and have low methylation fidelity, particularly in the differentiating mESCs. While 5-hmC and 5-mC tend to coexist, there is no significant correlation between 5-hmC levels and methylation fidelity. Our findings may shed new light on our understanding of the origins of methylation variations and the mechanisms underlying DNA methylation transmission.
Footnotes
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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.163147.113.
Freely available online through the Genome Research Open Access option.
- Received July 6, 2013.
- Accepted May 14, 2014.
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.
