“Early to bed and early to rise makes a man healthy, wealthy, and wise!” While many night owls happily ignore this sage advice and enjoy a few extra hours in bed in the mornings, a new study regarding DNA methylation dynamics in normal and cancer cells gives credence to the old axiom “If you snooze, you lose!” and may provide a means to track cellular aging!
More precisely, the bright eyed and bushy tailed researchers from the labs of Hui Shen, Peter W. Laird (Van Andel Research Institute), and Benjamin P. Berman (Cedars-Sinai Medical Center) have studied DNA methylation loss or hypomethylation at “lazier” regions of the genome, actually known as late-replicating regions. Previous studies have linked lamina-associated, late-replicating regions, otherwise known as partially methylated domains (PMDs), to various types of cancer and one study employed PMDs to trace the evolution of gene regulation in mammalian placentas. Fascinatingly, the author’s new findings establish that DNA methylation loss at late-replicating regions occurs progressively in most cells, beginning from even the earliest stages of development, and accurately tracks the number of cellular divisions made.
DNA Methylation Loss at Late Replicating Regions Tracks Cellular Aging
Here’s what the team discovered after applying advanced bioinformatics analysis to an extensive range of normal and cancerous mouse and human whole-genome bisulfite sequencing (WGBS) datasets, including tumor and adjacent normal data from eight common cancer types:
- A WCGW motif (where W = A or T) without neighboring CpGs (solo) represented the most hypomethylation-prone motif within late-replicating sequences
- The lack of nearby CpGs may diminish the ability of the DNA methyltransferase DNMT1 to re-methylate hypomethylated regions
- Additional analysis also discovered the absence of H3K36me3 at hypomethylated regions, a modification that actively recruits DNMT3B
- The late replication status of these regions may not provide the cell with time to re-methylate newly synthesized daughter strands during DNA replication
- A search for solo-WCGWs discovered previously undetected hypomethylation in the vast majority of healthy tissue types
- DNA methylation loss starts from embryonic development and progressively increases with chronological age
- solo-WCGW motif analysis in cancer cells demonstrated that higher mutation density and increased expression of proliferation-associated genes correlated to increased DNA methylation loss within late-replicating sequences
- Therefore, the authors propose that the loss of DNA methylation at solo-WCGWs within these regions tracks the accumulation of cell divisions and can precisely establish cellular age, which may be different to the chronological age of the host
Conclusions: The View from the Early Risers
Let’s finish with the thoughts of the three study leaders, who surely get up very early in the morning:
“Our cellular clock starts ticking the moment our cells begin dividing,” Laird said. “This method allows us to track the history of these past divisions and measure age-related changes to the genetic code that may contribute to both normal aging and dysfunction.”
“What is striking about the results from our new method is that they push back the start of this process to the earliest stages of in utero development,” Berman said. “That was completely surprising, given the current assumption that the process begins relatively late on the path to cancer. This finding also suggests that it may play a functional role relatively early in the formation of tumors.”
“Tissues with higher turnover rates are typically more susceptible to cancer development simply because there are more opportunities for errors to accumulate and force the change from a normal cell to a malignant one,” Shen said. “What we’re seeing is a normal process — cellular aging — augmented and accelerated once a cell becomes cancerous. The cumulative effect is akin to a runaway freight train.”
Quit your snoozing and be the early bird who catches the scientific worm at Nature Genetics, April 2018.