Cell Replication Changes the Epigenome in Ways that Connect to Cancer
Researchers here demonstrate that one can create a signature of replication-based epigenetic change in cells, and that this signature is stronger in old tissues and cancerous tissues. This leads to a view in which increased replication stress on cells in a tissue, meaning a tissue that is made up of cells that have divided more times on average, have shorter telomeres, and are closer to the Hayflick limit, creates an environment that is epigenetically predisposed towards cancer. Looking at this another way, aging is characterized by reduced stem cell function, meaning a lower pace of creation of daughter somatic cells to replace losses in a tissue. It seems inevitable that this must lead to a tissue in which the average somatic cell has replicated a greater number of times, and is thus more at risk of cancerous transformation.
Mutations are not the only, or perhaps even the most important, molecular events that result from cellular proliferation. We and others have shown that DNA methylation (DNAm) is also substantially altered as a direct function of cell division. Further, the epigenome has been shown to undergo dramatic changes with aging and is implicated in establishing, driving, and maintaining many cancers.
Coincidently, the DNAm changes observed in aging, cancer, and proliferation share some notable patterns. In general, they tend to be characterized by gains in methylation at promoters - especially those marked by polycomb group (PcG) factor targets - and loss of methylation in intergenic regions and repetitive elements. Thus, one hypothesis is that as cells replicate in aging tissues, they may also take on epigenetic signatures that are more cancer-like, making the leap to oncogenic transformation progressively more likely with time.
To date, the field has linked (i) age-related epigenetic changes and cancer phenomenon and (ii) replication-related changes to cancer, but little evidence exists linking all three simultaneously. It also remains unclear whether age-related replication-based changes are tumorigenic switches, and can perhaps predate the disease, or whether they are simply outcomes of cancer and uncontrolled proliferation. To test these hypotheses, we quantified a "replication fingerprint" in DNAm data derived from extensively passaged immortalized human cells using a de novo computational training platform.
This signature, termed CellDRIFT, increased with age across multiple tissues, distinguished tumor from normal tissue, was escalated in normal breast tissue from cancer patients, and was transiently reset upon reprogramming. In addition, within-person tissue differences were correlated with predicted lifetime tissue-specific stem cell divisions and tissue-specific cancer risk. Our findings suggest that age-related replication may drive epigenetic changes in cells and could push them toward a more tumorigenic state.