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Methylation Patterns in Pig Tissues Provide Clues to Obesity-Related Gene Regulation

NEW YORK (GenomeWeb News) – An international team led by investigators from Sichuan Agricultural University and BGI-Shenzhen has developed a DNA methylation atlas of pig fat and muscle tissues that is expected to aid studies into the epigenetics of obesity and related conditions.

As they reported online today in Nature Communications, the researchers profiled methylation patterns and gene expression profiles in 10 fat and muscle tissues from pigs belonging to three pig breeds.

The team has already used the resource to start exploring some of the epigenetic factors that contribute to obesity, focusing on sites in the genome where methylation varies between different breeds, individual pigs, and tissues. They also propose that the methylome map could serve as the basis for future studies of muscle and fat-related traits in pigs, humans, and other animals.

"The work performed here will serve as a valuable resource for future functional validation and aid in searching for epigenetic biomarkers for obesity prediction and prevention, and promoting further development of pig as a model organism for human obesity research," senior author Ruiqiang Li and colleagues wrote.

Li served as vice president and head of research and cooperation at BGI-Shenzhen from 2009 to 2011. He is now a bioinformatics researcher with Peking University's Biodynamic Optical Imaging Center and School of Life Sciences.

Past genome-wide association studies have started to track down some of the genetic players contributing to obesity. But while variants found in such studies have provided some insights into the biological underpinnings of obesity, they do not offer a complete picture of these processes and their regulation, researchers explained.

Even less is known about the DNA methylation patterns and other epigenetic factors that regulate obesity-related processes, they added, noting that the "current understanding of the roles of DNA methylation in the etiology of obesity remains fairly rudimentary."

The group decided to delve into such questions further, using the pig as a model organism. They specifically focused on adipose and skeletal muscle tissues because both are suspected of secreting metabolism-influencing signaling cytokines.

The two muscle tissues tested in the study represent white and red muscle, study authors noted, while the eight fat tissues were sampled from parts of the body known to have variable fatty acid profiles and fat cell content.

The team's sampling strategy also was designed to look at differences in so-called subcutaneous adipose tissue compared to fat in the abdomen and chest regions, known as visceral adipose tissue.

"[Visceral adipose tissues] have been recognized to be anatomically, functionally, and metabolically distinct from that of the compartmental [subcutaneous adipose tissues], and have been found to be related to a series of diseases, including cardiovascular disease, type II diabetes mellitus, and metabolic syndrome," the study's authors explained.

"Nonetheless," they added, "[subcutaneous adipose tissues] can have direct and beneficial effects on the control of body weight and metabolism."

Using methylated DNA immunoprecipitation sequencing, or MeDIP-Seq, with the Illumina HiSeq 2000, the researchers profiled methylation patterns in eight adipose tissues and two skeletal muscle tissues in nine male and nine female pigs each from the Landrace, Rongchang, and Tibetan breeds.

The three breeds represent a range of fat patterns, the team noted, because the Tibetan breed has been subject to relatively little artificial selection, while Landrace pigs have been selected for low-fat phenotypes and Rongchang pigs have been selected to have excess adiposity.

In addition to their sequence-based methylation profiling, the researchers looked at metabolic and phenotypic features in the pigs, which had been raised in similar environments and provided with free access to the same type of food. They also used the Agilent arrays to gauge gene expression levels in the same tissues tested for the methylation experiments.

By aligning filtered and quality controlled reads to the pig reference genome, the team identified sequences in the genome that were differentially methylated between pigs from different breeds, between male and female pigs, and between tissues taken from various sites in the body.

For instance, the researchers found that the methylation patterns in intermuscular fat tissues were unexpectedly similar to those in visceral fat tissues, hinting that intermuscular adipose tissue, like visceral adipose tissue, might have ties to metabolic and other diseases.

Their analysis of genes with differentially methylated regions in their promoters uncovered many genes from metabolism, lipid, and immune-related genes as well as genes coding for detoxifying enzymes.

Similarly, when they looked at how methylation patterns related to the location of pig versions of almost 300 genes implicated in obesity in humans, the investigators saw that roughly 80 percent of these pig orthologs fell in differentially methylated regions defined in the study.

So, too, did many of the genes associated with predicted fat and pork-quality related quantitative trait loci, including yet uncharacterized genes.

Although more research is needed to verify the involvement of these and other candidate genes identified in obesity, the study authors argued that results of the study overall support the notion that the pig model can help in teasing apart the genetics behind economically and medically important traits.

"In addition to providing new information for biomedical research, genomic/epigenomic studies of pigs may also help uncover the molecular basis that underlies economical traits in pig," they concluded, "which can be used to improve the efficiency of artificial selection, hence the production of healthier pork."

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