Quoted TextA six months exercise intervention influences the genome-wide DNA methylation pattern in human adipose tissue.
Epigenetic mechanisms are implicated in gene regulation and the development of different diseases. The epigenome differs between cell types and has until now only been characterized for a few human tissues. Environmental factors potentially alter the epigenome. Here we describe the genome-wide pattern of DNA methylation in human adipose tissue from 23 healthy men, with a previous low level of physical activity, before and after a six months exercise intervention. We also investigate the differences in adipose tissue DNA methylation between 31 individuals with or without a family history of type 2 diabetes. DNA methylation was analyzed using Infinium HumanMethylation450 BeadChip, an array containing 485,577 probes covering 99% RefSeq genes. Global DNA methylation changed and 17,975 individual CpG sites in 7,663 unique genes showed altered levels of DNA methylation after the exercise intervention (q<0.05). Differential mRNA expression was present in 1/3 of gene regions with altered DNA methylation, including RALBP1, HDAC4 and NCOR2 (q<0.05). Using a luciferase assay, we could show that increased DNA methylation in vitro of the RALBP1 promoter suppressed the transcriptional activity (p = 0.03). Moreover, 18 obesity and 21 type 2 diabetes candidate genes had CpG sites with differences in adipose tissue DNA methylation in response to exercise (q<0.05), including TCF7L2 (6 CpG sites) and KCNQ1 (10 CpG sites). A simultaneous change in mRNA expression was seen for 6 of those genes. To understand if genes that exhibit differential DNA methylation and mRNA expression in human adipose tissue in vivo affect adipocyte metabolism, we silenced Hdac4 and Ncor2 respectively in 3T3-L1 adipocytes, which resulted in increased lipogenesis both in the basal and insulin stimulated state. In conclusion, exercise induces genome-wide changes in DNA methylation in human adipose tissue, potentially affecting adipocyte metabolism.
Quoted TextFormer scientist here. OK, so DNA sequence is one thing that determines your "genes." Even though every cell in your body (except your sperm/eggs and immune cells) has the same chromosomes and the same DNA sequence, they look and behave drastically different! That's because there are many other factors that determine cell function/behavior, other layers to the DNA code, including euchromatin/heterochromatin, histone modification, transposons, long terminal repeats, and DNA methylation. DNA methylation, the addition of methyl groups to CpG islands in the DNA, changes the expression of genes, usually decreasing it (the decrease in the expression of one gene might increase the expression of another). These so called epigenetic changes influence cell behavior, and are ultimately responsible for cell identity, i.e. it's what makes your skin cell different from your heart cell.
The researchers found that regular exercise for 6 months changed the methylation states of many genes in our fat (adipose) cells, including 31 genes specific to obesity and diabetes type 2, reducing their expression level a small but significant amount, <10%. When they independently silenced a few of these specific genes with siRNA, expression of these genes was reduced by 50-70%, and the basal metabolic rate of and the rate of fat breakdown in fat cells increased drastically, by about 44%.
This is so cool. A recent paper showed drastic genetic changes in skeletal muscle cells, but this paper shows a similar biological change in fat cells. Not only do they identify the biological relevance of a few genes, by quantifying epigenetic change after regular exercise, these researchers showed that our genetics aren't static, but dynamically changing to respond to our environment; our environment fundamentally alters cell behavior at the genetic level. These changes may be heritable. Actually, I think it'd be interesting to see whether or not these specific DNA methylation states can be inherited from one generation to the next (a few papers have shown this already for other genes). Their research could explain why some people are more susceptible to type 2 diabetes than others, and help develop new genetic screens to test for one's susceptibility to type 2 diabetes. We might figure out whether or not the effects of regular exercise could be passed on to our offspring! It's interesting to note that only a handful of the genes found to be affected by exercise had to do with obesity and type 2 diabetes. The other genes might be responding to or be affected by inflammation or other indirect sequelae of exercise and may have biologically significance in other cell types.
It's important to note that the paper does not demonstrate the epigenetic changes are stably expressed. DNA methylation is reversible. How long do these exercise-induced epigenetic marks remain on the DNA? Do they remain after 3 days, 3 months, if at all? The more stable the change, the more biologically relevant it is. These are really important questions!