The year is coming to an end and you know what that means — it’s time to promise yourself that next year is your year to get fit. But if you’re one of the many who never quite live up to their lofty activity goals, don’t be too hard on yourself; your epigenetics may be working against you!
Sure, genetics and social factors are important, but a new study from the lab of Robert Waterland (Baylor College of Medicine, USA) suggests that DNA methylation in the arcuate nucleus of the hypothalamus (ARH), a brain area that contains hormone-producing AgRP neurons, is essential to an animal’s willingness to exercise.
The talented team generated AgRP neuron-specific Dnmt3a knockout mice (KO), that had reduced 5mC and 5hmC immunofluorescence in their ARH, but they were surprised to find that the animals weighed the same, consumed the same amount of food, and had similar endurance when forced to run on a treadmill. The difference appeared when the animals had free access to an exercise wheel; KO mice opted out of exercise and spent only half of the time running that wildtype mice did.
The resourceful researchers resolved to take a closer look, used fluorescence activated cell sorting (FACS) to collect neurons from the ARH, and found that:
- 1681 genes are upregulated and 2063 are downregulated according to RNA-seq
- Unexpectedly, there are three times more hypermethylated DNA regions (DMRs) in the Dnmt3a knockout mice neurons than hypomethylated, according to whole genome bisulfite sequencing (WGBS)
Without a single-cell WGBS dataset to compare to, the researchers developed a new approach to deal with their DMR dilemma. They divided the genome into 100kb bins and then grouped all the WGBS reads with identical methylation levels within the bin together and labelled them as coming from the same type of cell. If the read group was methylated in wildtype mice, but not in KOs, then it probably came from the AgRP neurons, and vice versa. Using this read-level analysis, the savvy scientists found that:
- Genes that are located within non-AgRP methylation bins overlap with genes that are expressed in non-AgRP neurons, and are enriched for SMAD binding and TGF-β signalling molecules
- The promoters of bone morphogenic protein 5 and 7 (Bmp5 and Bmp7), which are ligands in the TGF-β pathway, are less methylated and more expressed in KO neurons, which they confirmed by bisulfite pyrosequencing and fluorescence in situ hybridization, respectively
Waterland shares “Our findings suggest that epigenetic mechanisms, such as DNA methylation, that are established in the brain during fetal or early postnatal life, play a major role in determining individual propensity for exercise. Nowadays, as decreases in physical activity contribute to the worldwide obesity epidemic, it is increasingly important to understand how all of this works.”
If wheel-running isn’t on your list this New Year, you can resolve to read the original article in Nature Communications, December 2019.