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Minding methylation
by Kelsey Kaustinen  |  Email the author


SACRAMENTO, Calif.—A team of researchers from the University of California, Davis (UC Davis) and the University of British Columbia has discovered a facet of methylation that could provide new information into the genetics of human development and cancer. While working with the placenta in hopes of identifying biomarkers for autism, the team found that 37 percent of the placental genome contains regions of lower methylation known as partially methylated domains (PMDs), in which gene expression is turned off. In contrast, most human tissues feature high methylation in 70 percent of the genome.
"I like to think of epigenetics as a layer on top of your genetic code," Janine LaSalle, professor of medical microbiology and immunology at UC Davis and senior author of the paper, said in a press release. "It's not the DNA sequence but it layers on top of that—and methylation is the first layer. Those layers provide a lot of information to the cells on where and when to 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 genes are expressed. How and when genes are activated or deactivated is significant in terms of human development and the development of cancer and genetic defects due to environmental toxins.  
Up to this point, PMDs have been found in cultured cell lines, but not in regular adult human tissue, though LaSalle says it is possible 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 in between a stem cell state and a fully differentiated state where [cells] seem to have them."  
"People are still figuring out what these PMDs are and what they mean, but it seems to be a landscape feature of the methylome that's really 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 a placenta's genome, which encompasses 3,815 genes (about 17 percent of all genes). Genes located in regions of low methylation are less likely to be transcribed into proteins. In addition, PMDs also contain more highly methylated CpG islands—genomic regions that feature a large number of cytosine-guanine pairs 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, the promoters boast higher methylation in the PMD state.
"I think that's interesting from the perspective of what's known about methylation in cancer, because hypermethylation of promoters is usually interpreted as the silent signal, where it actually may be location to these PMDs which is the reason for the silencing, not the hypermethylation of the promoter," she notes.  
This new way to study PMDs could answer some questions about a variety of diseases and conditions, including cancer. Placental tissue shares some invasive characteristics often link to cancer, and several cancers such as breast and colon cancer feature widespread PMDs. Methylation studies could provide clues about other genetic defects as well.  
"Methylation patterns are like fingerprints, showing which tissue that DNA is derived from," LaSalle commented. "You can't get that information from just the DNA sequence. As a result, methylation studies could be 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 in development and epigenetics. Moving forward, the research team will seek to figure out more about PMDs and possible therapeutic areas for which they could provide answers, and will continue working with placentas as an epigenetic source for biomarkers that could predict autism. Among the genes located in PMDs are several linked with neuronal development, including autism. LaSalle noted in a press release that this work with PMDs have provided "a series of snap shots from a critical period where we think environmental factors are playing a role in the developing brain."  
The paper appeared online in the Proceedings of the National Academy of Sciences.

Code: E04241304



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