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DNA methylation loss in late-replicating domains is linked to mitotic cell division

Nature Genetics volume 50, pages 591–602 (2018)Cite this article

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Abstract

DNA methylation loss occurs frequently in cancer genomes, primarily within lamina-associated, late-replicating regions termed partially methylated domains (PMDs). We profiled 39 diverse primary tumors and 8 matched adjacent tissues using whole-genome bisulfite sequencing (WGBS) and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context (‘solo-WCGWs’) identified previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increased with age, beginning during fetal development, and appeared to track the accumulation of cell divisions. In cancer, PMD hypomethylation depth correlated with somatic mutation density and cell cycle gene expression, consistent with its reflection of mitotic history and suggesting its application as a mitotic clock. We propose that late replication leads to lifelong progressive methylation loss, which acts as a biomarker for cellular aging and which may contribute to oncogenesis.

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Fig. 1: Solo-WCGW CpGs are prone to hypomethylation.
Fig. 2: Most PMDs are shared across cancer and normal tissues.
Fig. 3: Most PMDs are shared across developmental lineages.
Fig. 4: Most PMDs are shared across developmental lineages in mouse.
Fig. 5: PMD hypomethylation emerges during embryonic development.
Fig. 6: PMD hypomethylation is associated with chronological age.
Fig. 7: PMD hypomethylation is linked to mitotic cell division in cancer.
Fig. 8: Replication timing and H3K36me3 contribute independently to methylation maintenance.

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Acknowledgements

We thank T. Hinoue and H. Noushmehr for help selecting TCGA WGBS samples based on analysis of other TCGA data types and H. Goodridge and D.-C. Lin for useful discussions and comments. We thank The Cancer Genome Atlas Research program office, especially K. Shaw, for helping to get the WGBS project up and running. We also thank the members of the TCGA Research Network along with the dozens of other research groups that generated the published datasets that were used here to gain new insights. This project was supported by the Van Andel Research Institute, the Cedars-Sinai Center for Bioinformatics and Functional Genomics and the Samuel Oschin Comprehensive Cancer Institute, and the University of Southern California USC Epigenome Center. The work was funded by the following grants: National Institutes of Health/National Cancer Institute grants U24 CA143882 (P.W.L., B.P.B., H.Q.D., and H.S.); R01 CA170550 (P.W.L.); U01 CA184826 (B.P.B.); U24 CA210969 (P.W.L., B.P.B., and H.S.), Ovarian Cancer Research Fund Grant 373933 (H.S.), and National Institutes of Health/National Human Genome Research Institute grant R01 HG006705 (B.P.B.).

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  1. These authors contributed equally: Wanding Zhou and Huy Q. Dinh. These authors jointly directed this work: Hui Shen, Peter W. Laird and Benjamin P. Berman.

Authors and Affiliations

  1. Center for Epigenetics, Van Andel Research Institute, Grand Rapids, MI, USA

    Wanding Zhou, Hui Shen & Peter W. Laird

  2. Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Huy Q. Dinh & Benjamin P. Berman

  3. Van Andel Institute, Grand Rapids, MI, USA

    Zachary Ramjan

  4. USC Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    Daniel J. Weisenberger & Charles M. Nicolet

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Contributions

H.S., P.W.L., and B.P.B. conceived the study. C.M.N., P.W.L., and B.P.B. oversaw the data generation and data quality control, with assistance from D.J.W. Z.R. automated the next-generation sequencing analysis and quality control steps, and submission of data to NCI repositories. W.Z., H.Q.D., H.S., and B.P.B. performed computational analysis and produced figures. W.Z., H.S., P.W.L., and B.P.B. wrote the manuscript, with significant contributions from H.Q.D. H.S., P.W.L., and B.P.B. supervised the project.

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Correspondence to Hui Shen, Peter W. Laird or Benjamin P. Berman.

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Supplementary Table 1

Meta-information and sources of WGBS samples reported and analyzed

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Zhou, W., Dinh, H.Q., Ramjan, Z. et al. DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat Genet 50, 591–602 (2018). https://doi.org/10.1038/s41588-018-0073-4

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