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.

克隆调控程序的传播有助于癌症的发展。人们对表观遗传机制如何与遗传驱动因子相互作用以塑造这一过程了解甚少。在这里，我们结合Luria-Delbrück实验设计对转录和DNA甲基化进行单细胞分析，以证明多种类型的癌细胞中存在克隆稳定的表观遗传记忆。克隆结肠癌细胞群的纵向转录和遗传分析显示上皮到间充质转录身份的频谱缓慢漂移，这似乎与遗传变异无关。DNA甲基化景观与这些身份相关，但也反映了独立的类似时钟的甲基化损失过程。甲基化变化可以解释为整体反式的影响在大多数情况下影响作用的因素。然而，对于一类特定的启动子，特别是癌症的睾丸抗原，去阻抑与顺式甲基化的丧失有关，并可能由顺式丧失。这项研究表明如何通过表观遗传记忆使癌细胞中的基因亚克隆结构多样化。