CHARLOTTE, NC (GenomeWeb News) – In the search for disease-related epigenetic patterns that can be detected with a simple blood test, researchers are looking more closely at a group of epigenetic marks known as metastable epialleles, attendees heard today at the American College of Medical Genetics and Genomics annual clinical meeting.
Speaking during a plenary session on developmental epigenetics and human disease, Robert Waterland, a pediatrics and molecular and human genetics researcher at Baylor College of Medicine, described studies being done on epigenetic regulation with an eye towards environmental factors that influence these processes, including maternal nutrition.
The goal of such research, he said, is to "understand, at the most fundamental level, how environmental influences in early development shape the regulation of the genome for a lifetime."
In particular, Waterland highlighted mouse and human studies of metastable epialleles — sites in the genome with methylation levels that vary from one individual to the next, but which remain stable across cell types from each individual.
Using the agouti locus in mice as an example, he explained how nutritional factors during fetal development can interact with these metastable epialleles to alter methylation patterns, which, in turn, can affect gene expression and phenotype across an organism's lifetime.
While such epigenetic marks are relatively rare in the genome and are expected to have a more limited role in disease than tissue-specific cytosine methylation, he explained, the stability of methylation at these sites means metastable epialleles that do influence health or disease would be easily detectable using DNA from blood samples.
In their previous efforts to find such sites in the human genome, researchers have used a method called methylation-specific amplification microarray, or MSAM, which relies on the use of methylation sensitive restriction enzymes and microarrays.
In a study published online in PLoS Genetics in late 2010, for example, Waterland and his collaborators used MSAM to compare methylation sites in blood and hair follicle samples from eight Caucasian individuals. In the process, they found 40 loci in the human genome where methylation patterns appeared to vary between individuals but remained stable in multiple tissues from the same individual.
Validation experiments done using post-mortem liver, kidney, and brain tissue samples from eight Vietnamese individuals verified a subset of these candidate sites as plausible metastable epialleles.
That study found that methylation levels at some of the apparent metastable epialleles was set during fetal development and influenced by maternal nutrition — something that the team tested by looking at cytosine methylation at the sites in relation to season-of-conception in children from a rural Gambian community where maternal nutrition shifts dramatically between the rainy and dry seasons.
Moreover, researchers suspect that this altered epigenetic regulation may help to explain differences in preterm birth rates and gestational size that have been reported in the Gambian community between children born during the rainy and dry seasons.
The team is continuing to look for more metastable epialleles in humans with the goal of finding some that are associated with human disease, Waterland said.
He noted that they are continuing to use methylation-specific amplification for their current studies, and researchers are now coupling that approach with high-throughput sequencing rather than microarrays.
In addition to the metastable epiallele studies described, Waterland also touched on some of the work that his group and others are doing to look at cell type-specific cytosine methylation, its environmental regulation, and influence on obesity in humans.