Journal
NATURE GENETICS
Volume 52, Issue 7, Pages 709-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41588-020-0645-y
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Funding
- European Research Council [724824]
- Israel Science Foundation
- Chan Zuckerberg Initiative
- European Research Council (ERC) [724824] Funding Source: European Research Council (ERC)
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Propagation of clonal regulatory programs contributes to cancer development. It is poorly understood how epigenetic mechanisms interact with genetic drivers to shape this process. Here, we combine single-cell analysis of transcription and DNA methylation with a Luria-Delbruck experimental design to demonstrate the existence of clonally stable epigenetic memory in multiple types of cancer cells. Longitudinal transcriptional and genetic analysis of clonal colon cancer cell populations reveals a slowly drifting spectrum of epithelial-to-mesenchymal transcriptional identities that is seemingly independent of genetic variation. DNA methylation landscapes correlate with these identities but also reflect an independent clock-like methylation loss process. Methylation variation can be explained as an effect of globaltrans-acting factors in most cases. However, for a specific class of promoters-in particular, cancer-testis antigens-de-repression is correlated with and probably driven by loss of methylation incis. This study indicates how genetic sub-clonal structure in cancer cells can be diversified by epigenetic memory. Longitudinal single-cell analysis of transcription and DNA methylation dynamics in cancer cell lines suggests a clonally stable epigenetic memory. Colon cancer cells show a spectrum of epithelial-to-mesenchymal identities that seems independent of genetic variation.
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