Single-cell analysis of clonal maintenance of transcriptional and epigenetic states in cancer cells

Zohar Meir, Zohar Mukamel, Elad Chomsky, Aviezer Lifshitz, Amos Tanay*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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–Delbrück 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 global trans-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 in cis. This study indicates how genetic sub-clonal structure in cancer cells can be diversified by epigenetic memory.

Original languageEnglish
Pages (from-to)709-718
Number of pages10
JournalNature Genetics
Issue number7
StatePublished - 1 Jul 2020
Externally publishedYes


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