Cell Rep answers unanswered questions: DNA methylation affects replication and genome organization

The genome of most cancer cells has a much lower degree of methylation than that of normal cells.

The research was published in Cell Reports on September 21, "An elegant analysis of the effects of DNA methylation on 3-D genome organization," Toronto Price Margaret Emma Bell, a bioinformatician at the Pricess Margaret Cancer Center, said she was not involved in the study

For the past 25 years or so, Clark and her team at the Gavin Institute of Medical Research in Australia have been interested in the relationship between epigenetics and cancer

Genome methylation is a fingerprint of the cell, and the identity of the cell is also guided into three-dimensional space by the genome organization to help determine which genes are expressed

The researchers started with two versions of the same cell: one was a normal cancer cell line, and the other was to knock out two DNA methyltransferases, which replicate the methylation patterns of DNA strands to those produced during the replication process.

The research team found that hypomethylation leads to changes in replication time, that is, whether a region replicates early or late during the replication process

“It’s shocking that when they removed the methyltransferase, they were able to see these differences in replication time,” said Christine Kuccinotta, who was at Fred Hutchinson Cancer in Seattle.

These changes in replication time also seem to affect the three-dimensional organization of genomic regions, especially so-called partially methylated regions, which have lower DNA methylation levels in conventional cancer cells

Clark wrote: "These findings highlight the role of epigenetics in cancer progression, which may help explain how cancer becomes more heterogeneous with each cell division

Clark's research team also found evidence that the cell can mitigate the effects of methylation reduction to a certain extent

This work confirmed the connection between DNA methylation, histone methylation, transcription changes and timing of replication, said Susan Gasser, a molecular biology at the University of Basel Scientists did not participate in this research

The next step will be a "comparison between healthy cells, precancerous cells and cancer cells," Bell said.