The dynamics of DNA methylation fidelity during mouse embryonic stem cell self-renewal and differentiation.
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.
Laboratory of Genome Variation and Precision Biomedicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
Lei
L
Zhao
Epigenomics and Computational Biology Lab, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia 24060, USA;
Ming-An
MA
Sun
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA;
Zejuan
Z
Li
Laboratory of Genome Variation and Precision Biomedicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
Xue
X
Bai
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA;
Miao
M
Yu
Epigenomics and Computational Biology Lab, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia 24060, USA;
Min
M
Wang
Laboratory of Genome Variation and Precision Biomedicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
Liji
L
Liang
Laboratory of Genome Variation and Precision Biomedicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
Xiaojian
X
Shao
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA;
Stephen
S
Arnovitz
Laboratory of Genome Variation and Precision Biomedicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
Qianfei
Q
Wang
Department of Chemistry and Institute for Biophysical Dynamics, The University of Chicago, Chicago, Illinois 60637, USA;
Chuan
C
He
Laboratory of Genome Variation and Precision Biomedicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
Xuemei
X
Lu
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, Illinois 60637, USA;
Jianjun
J
Chen
Laboratory of Genome Variation and Precision Biomedicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; Epigenomics and Computational Biology Lab, Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, Virginia 24060, USA; Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24060, USA davidxie@vt.edu jchen@bsd.uchicago.edu luxm@big.ac.cn.
Hehuang
H
Xie
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D018899:CpG Islands; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000502:physiology*; D044127:Epigenesis, Genetic; D015870:Gene Expression; D006657:Histones / Q000378:metabolism; D051379:Mice; D011485:Protein Binding; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000378:metabolism
D006657:Histones; D014157:Transcription Factors