While two copies of genes--one from each parent--is usually a good thing, for about a hundred genes, one copy--either the mother's or the father's copy--is silenced, a process known as genomic imprinting. This silencing was thought to be stable. But this silence doesn't last in certain cell types, finds a mouse study published September 20 in Cell Reports.
Whitehead Institute researchers made the discovery by using new technology that monitors changes in epigenetic marks on DNA over time (doi: 10.1016/j.cell.2015.08.046). With this resource, the researchers looked at a specific imprinted methylation mark (IG-DMR) in mouse embryonic stem cells that, if not in place on either the maternal or paternal copy of DNA, causes early embryonic death. As mice grew into adulthood, the investigators noticed that the imprinted methylation marks started to vary from cell to cell and that this variation differed depending on the cell type (e.g., retina cells kept much of the genomic imprinting while intestinal cells did not).
The study's findings indicate that these epigenetic marks can be regulated in adult tissues and challenge the hypothesis that genomic imprinting is maintained over time. Based on the analysis, it does appear that silencing one set of parental genes is essential during development, but afterwards, the silencing begins to vary by cell and cell type. In cells where the epigenetic marks are lost, the genes from the silenced parental DNA either cause overexpression or non-expression of those genes.
"There seems to be a requirement for more fine-tuned gene expression of imprinting in different tissues throughout development and in adulthood, which is a very exciting idea," says first author Yonatan Stelzer, a postdoctoral fellow in the lab of senior author Rudolf Jaenisch, of the Whitehead Institute for Biomedical Research and MIT.
The researchers plan to investigate why there could be cell type differences in genomic imprinting over time, whether there are any functional consequences of changes in imprinting, and whether environmental factors play a role in regulating these changes.
"It's essentially the first time that we can see epigenetic changes during development in vivo, this opens up a lot of questions because DNA methylation plays a role in key processes that we did not have a readout for," Stelzer says. "Now we can start applying unbiased screens of small molecules to affect this epigenetic phenomenon and ask basic questions on the role of DNA methylation changes in early development and disease."
This study was supported by the National Institutes of Health, a Human Frontier Postdoctoral Fellowship, and a NARSAD Young Investigator Fellowship. Rudolf Jaenisch is an advisor to Stemgent and a co-founder of Fate Therapeutics and Fulcrum Therapeutics.
Cell Reports, Stelzer et al.: "Parent-of-origin DNA methylation dynamics during mouse development" http://www.cell.com/cell-reports/fulltext/S2211-1247(16)31147-0
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