DNA methylation influences the replication and organization of the genome

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MMost cancer cells have much less methylated genomes than those of normal cells, but whether this loss of methylation, an epigenetic process, has functional significance for cells has long been an unanswered question. Now researchers show that cells that loss of DNA methylation throughout the genome alters the timing of DNA replication and alters the shape of 3-D compartmentalization of DNA, which helps orient the gene expression.

The study, published on September 21 in Cell reports, is “an elegant dissection of the impact of DNA methylation on the organization of the 3-D genome,” says Emma Bell, a bioinformatician at the Pricess Margaret Cancer Center in Toronto who was not involved in the work. “It’s really important to show how aberrant DNA methylation, which is a common cancer artefact, impacts higher order genome organization and DNA replication.”

For about 25 years, Susan Clark and her group at the Garvan Institute of Medical Research in Australia have been interested in how epigenetics are involved in cancer. As most cancer cells lose DNA methylation throughout the genome, it was surprising how little was known about the overall consequences of hypomethylation, Clark explains in an email to The scientist.

Methylation of the genome is a kind of fingerprint for a cell, and cell identity is also guided by the organization of the genome into 3-D compartments that help determine which genes are expressed. Clark and his colleagues hypothesized that DNA methylation plays a role in maintaining this genomic architecture and, in the new study, used colorectal cancer cells to investigate this hypothesis.

The researchers started with two versions of the same cells: a normal cancerous cell line and one with knockouts of two DNA methyltransferase enzymes, which mimic the methylation pattern of one strand of DNA onto generated daughter DNA strands. during replication. Cells lacking DNA methyltransferases exhibited reduced methylation levels genome-wide. Then, in individual cells of the two cell lines, they mapped DNA replication throughout the genome and studied the 3-D organization of the genomes.

The team found that hypomethylation caused a change in the replication schedule – that is, how sooner or later a region was copied during replication. Most of these changes were moderate: regions replicated slightly earlier or later in genomes that lacked methylation. But more than three percent of the hypomethylated genomes were replicated much earlier or later than in cells with intact DNA methyltransferases.

It is “surprising that they could have seen these differences in the timing of replication when they got rid of methyltransferases,” says Christine Cucinotta, who studies chromatin architecture at the Fred Hutchinson Cancer Research Center in Seattle and does did not participate in the work. The replication schedule, she adds, is “generally quite robust outside of transitions in cell fate.”

These changes in the replication schedule also appeared to affect the 3-D organization of genomic regions, particularly in the so-called partially methylated domains, which are places that in ordinary cancer cells have lower levels of methylation of the genome. ‘DNA. This DNA architecture, in turn, plays a role in gene expression. For example, when DNA replication shifted earlier in hypomethylated cells, there was a shift to 3-D structures indicating more active gene expression, which the researchers also observed. They determined that the loss of precision in replication and associated changes in 3-D compartmentalization and gene expression particularly affected genes linked to cancer.

“These results highlight the role of epigenetics in cancer progression which may help explain how cancers can become more heterogeneous with each cell division,” writes Clark.

Clark’s group also found evidence suggesting that the cell may reduce the impact of reduced methylation to some extent. In regions of hypomethylated cells where replication was delayed, the team saw an increase in DNA bands in which histone H3 had been altered by both chromatin repressive markings and those associated with DNA. more accessible for transcription. This new double layer of regulation can “suppress the overall disruption of gene transcription across compartments,” explains Clark. The scientist.

This work confirms the proposed link between DNA methylation, histone methylation, changes in transcription and replication schedule, explains Susan Gasser, molecular biologist affiliated with the University of Basel and the Friedrich Miescher Institute of biomedical research in Switzerland which did not participate in the study. “The important thing is not to say that DNA methylation is the trigger for the whole cascade,” she adds. “I think we see that there is a balance between these four things, and that there are regions of the genome that are hypersensitive to. . . these fluctuations.

A next step would be “a comparison between healthy cells, precancerous cells and cancer cells,” Bell said. The scientist. “What we’ve portrayed here is a picture of cancer and aberrant DNA methylation, but it doesn’t happen all at once. I would like to see what happens in DNA methylation, 3D genome organization and DNA replication timing during the process of oncogenesis.


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