Cell division history is linked to disorder in DNA chemical marks differently across blood, gut, and brain
Cell division history is linked to disorder in DNA chemical marks differently across blood, gut, and brain
On August 24, bioRxiv published a preprint, an article that has not yet undergone peer review, based on 1 531 healthy human samples from 14 tissue and cell groups. After accounting for the proportions of different cell types in each sample, the authors found that estimated stem cell division history explained about 90% of the variation in epigenetic noise that their overall statistical model could explain.
DNA methylation is a chemical mark found at certain DNA sites. In data from a single sample, some sites may appear methylated while others do not. A greater mixture of these states produces higher Shannon entropy, which the authors used as a measure of epigenetic noise. In whole tissue, this variation can also arise because samples contain different proportions of various cell types. The authors estimated these proportions and included them in their calculations before comparing chronological age with division history.
To estimate accumulated cell divisions, they used 163 CpG sites, which are short DNA sequences where the letters C and G occur next to each other. From methylation at these sites, the researchers calculated a measure of past stem cell turnover and compared it with chronological age.
The difference became apparent when the authors analyzed the results by genomic region and tissue. CpG islands are DNA regions with particularly dense concentrations of CpG sites, often located near regions that regulate gene activity. Their entropy was 23% lower on average than that of CpG sparse regions. In blood and colon, division history accounted for more than 90% of the model explained variance around CpG islands. In the brain, its contribution within these islands reached 99%. At approximately a thousand DNA bases beyond their boundaries, chronological age explained 47–68% of the local variation.
Data from the SCARLET model had already linked age related DNA marks in blood to the division pattern of hematopoietic stem cells. The new analysis compared tissues with different turnover rates. It found that the same methylation measure may reflect division history around CpG islands and an age related effect in other regions of the brain.