Minding methylation

UC Davis and University of British Columbia researchers unveil new discoveries about methylation, including partially methylated domains, which may lead to more answers about genetic development and defects such as cancer

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SACRAMENTO, Calif.—A team of researchers from the University of California, Davis (UC Davis) andthe University of British Columbia has discovered a facet of methylation thatcould provide new information into the genetics of human development andcancer. While working with the placenta in hopes of identifying biomarkers forautism, the team found that 37 percent of the placental genome contains regionsof lower methylation known as partially methylated domains (PMDs), in whichgene expression is turned off. In contrast, most human tissues feature highmethylation in 70 percent of the genome.
"I like to think of epigenetics as a layer on top of yourgenetic code," Janine LaSalle, professor of medical microbiology and immunologyat UC Davis and senior author of the paper, said in a press release. "It's notthe DNA sequence but it layers on top of that—and methylation is the firstlayer. Those layers provide a lot of information to the cells on where and whento turn on the genes."
Methylation is an epigenetic process in which a methyl group(a group of carbon and hydrogen atoms) attaches to DNA and controls how genesare expressed. How and when genes are activated or deactivated is significantin terms of human development and the development of cancer and genetic defectsdue to environmental toxins.
Up to this point, PMDs have been found in cultured celllines, but not in regular adult human tissue, though LaSalle says it ispossible they can be found somewhere. Stem cells, she notes, don't have PMDs,since stem cells feature high methylation, so it seems to be "somewhere inbetween a stem cell state and a fully differentiated state where [cells] seemto have them."
"People are still figuring out what these PMDs are and whatthey mean, but it seems to be a landscape feature of the methylome that'sreally only there probably transiently in development and shows up in cancer,"says LaSalle. "They're interesting to try and figure out why they're there,what they mean and what it means for the genes that reside within them."

The study found that PMDs comprised 37 percent of aplacenta's genome, which encompasses 3,815 genes (about 17 percent of allgenes). Genes located in regions of low methylation are less likely to betranscribed into proteins. In addition, PMDs also contain more highly methylatedCpG islands—genomic regions that feature a large number of cytosine-guaninepairs and are associated with gene transcriptional silencing of promoters.
LaSalle says the findings on promoters were a surprise,because while the genes located in PMDs tend to have lower methylation, thepromoters boast higher methylation in the PMD state.
"I think that's interesting from the perspective of what'sknown about methylation in cancer, because hypermethylation of promoters isusually interpreted as the silent signal, where it actually may be location tothese PMDs which is the reason for the silencing, not the hypermethylation ofthe promoter," she notes.
This new way to study PMDs could answer some questions abouta variety of diseases and conditions, including cancer. Placental tissue sharessome invasive characteristics often link to cancer, and several cancers such asbreast and colon cancer feature widespread PMDs. Methylation studies couldprovide clues about other genetic defects as well.
"Methylation patterns are like fingerprints, showing whichtissue that DNA is derived from," LaSalle commented. "You can't get thatinformation from just the DNA sequence. As a result, methylation studies couldbe a very rich source for biomarkers."
More work with methylation and PMDs needs to be done,LaSalle notes, in terms of finding out the nature of PMDs and their impact indevelopment and epigenetics. Moving forward, the research team will seek tofigure out more about PMDs and possible therapeutic areas for which they could provideanswers, and will continue working with placentas as an epigenetic sourcefor biomarkers that could predict autism. Among the genes located in PMDs areseveral linked with neuronal development, including autism. LaSalle noted in apress release that this work with PMDs have provided "a series of snap shotsfrom a critical period where we think environmental factors are playing a rolein the developing brain."
The paper appeared online in the Proceedings of the National Academy of Sciences. 

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