Gene Involved in Energy Consumption Is Epigenetically Modified in Type 2 Diabetics

The PGC-1α gene, which controls other genes that regulate cells’ metabolism of glucose, is modified and has reduced expression in patients with early-onset diabetes, according to a research group at Karolinska Institutet. They say that their findings could help explain the influence of environmental factors on type 2 diabetes.

The study is published in the September 2 issue of Cell Metabolism in a paper titled “Non-CpG Methylation of the PGC-1α Promoter through DNMT3B Controls Mitochondrial Density”.

Epigenetic modification through DNA methylation is implicated in metabolic disease. In the current research, the scientists used whole-genome promoter methylation analysis of skeletal muscle from normal glucose-tolerant and type 2 diabetic subjects.

They identified the PGC-1α gene and found that the highest proportion of cytosine methylation within PGC-1α was found within non-CpG nucleotides. Moreover, non-CpG methylation was acutely increased in human myotubes by exposure to tumor necrosis factor-α or free fatty acids but not insulin or glucose. 

The team also demonstrated that DNA methylation occurs rapidly when cells from healthy people are exposed to certain factors associated with diabetes, such as raised levels of free fatty acids and cytokines.

“This type of epigenetic modification might be the link that explains how environmental factors have a long-term influence on the development of type 2 diabetes,” says Juleen Zierath, who led the study. “It remains to be seen whether the DNA methylation of this gene can be affected by, say, dietary factors.” 

The researchers note that selective silencing of the DNA methyltransferase 3B (DNMT3B)—but not DNMT1 or DNMT3A—prevented non-CpG methylation of PGC-1a and decreased mtDNA and PGC-1α mRNA. Therefore, they suggest that DNMT3B is linked to PGC-1α methylation.