Heat Sensitivity Embedded in DNA Methylation?
People’s sensitivity to painful heat may be determined, in part, from the pattern of methyl groups found along their DNA, according to a study published February 4 in Nature Communications. Led by Jordana Bell and Tim Spector of Kings College London, United Kingdom, the study analyzed the methylation patterns across the genomes of 100 people, including 25 pairs of identical twins who differed in their heat pain thresholds. The results highlighted nine differentially methylated regions, including the promoter for the transient receptor potential channel A1 (TRPA1) gene, which encodes an ion channel activated by painful stimuli.
The findings add to the small but growing pile of data implicating epigenetic modifications to DNA in pain. Such modifications influence gene expression of the underlying DNA, without altering the DNA sequence itself. For example, methyl groups suppress gene expression, so that patterns of methylation may program the spectrum of genes on or off in a given tissue and contribute to susceptibility to disease or conditions such as chronic pain (reviewed in Denk and McMahon, 2012).
“We’ve got nothing like this in the field at the moment,” said Sandrine Géranton, of University College London, United Kingdom, referring to the large, unbiased screen for methylation done in the study.
Géranton, who was not involved in the study, investigated whether epigenetic modifications in the spinal cord promote chronic pain (see PRF related news story), and other studies have found signs of epigenetic involvement in pain in pre-selected genes (see PRF related news story).
But the new study provides the first comprehensive look across the entire genome. “We just went in blind, without any prior assumptions about which genes play a role,” Bell told PRF.
Epigenetic tags are added to or removed from DNA as a result of genetic or environmental influences. Much of the epigenetics buzz stems from the latter case, in which life’s experiences mold gene activity. To zero in on environmental contributors, the study included identical twins from the large collection founded by Spector: Any methylation differences between co-twins would have to result from differences in lifestyle or experience.
The nine regions highlighted by the study don’t include a gene with undisputed links to heat sensitivity. TRPA1 is activated by chemical irritants and cold stimuli, but is not known to transduce heat in mammals. For Géranton, the lack of an established heat sensor in the list undermines the relevance of the highlighted regions. “When you don’t have an internal control like that, everything else seems a bit up in the air,” she said.
But others find the overall results compelling, even if TRPA1 doesn’t turn out to be involved. “This is an important proof of concept showing that differences in methylation are related to pain sensitivity,” said Laura Stone of McGill University, Montreal, Canada, who studies epigenetic contributors to pain.
Millions of methyl marks
First author Bell and colleagues began with 25 pairs of monozygotic twins whose pain thresholds to heat applied on the arm differed by at least 2 degrees centigrade. The researchers extracted the methylated portions of the genome from blood cells of the twins and sequenced them, thus giving the precise locations of the methyl groups.
The researchers then measured the amount of methylation across discrete, 1 kilobase regions in the genome for each twin, as well as for 50 unrelated individuals, coming up with correlations between methylation levels and pain thresholds. Of 50.2 million regions assayed, nine gave statistically significant correlations, with methylation usually increasing as pain sensitivity increased.
The most significant correlation came from the promoter of TRPA1, with increased methylation in subjects with more heat sensitivity. This suggests that lower TRPA1 gene expression would be associated with heat sensitivity, and this was somewhat borne out by data on TRPA1 messenger RNA levels in skin biopsies from a separate group of twins. Though it’s not immediately clear why less TRPA1 would be linked to more heat sensitivity, the researchers suggested it may reflect something about TRPA1’s interactions with the heat-sensing channels TRPV1, TRPV2, and TRPV3. These, too, were differentially methylated in the study, though they did not reach the criterion level of statistical significance.
One caveat of the study was that methylation patterns in blood may not be the same as those in pain-relevant tissues such as skin or nerve cells. However, comparisons in postmortem brain tissue from two twins suggested blood was a reasonable proxy. Among the top 100 differentially methylated regions, a significant, positive correlation emerged between blood-based and brain-based levels of methylation.
Within twin
Direct comparisons between co-twins revealed the same relationships between methylation and heat sensitivity for each of the nine regions fingered in the larger analysis. In a ranking of the associations by p values, TRPA1 did not fall in the top tier in this subgroup. Still, the consistency in the direction of the effects in genetically identical co-twins suggests that the methylation patterns do result from environmental influences, which could include lifestyle or even past painful experiences.
Methylation patterns in these nine regions were relatively stable over time, too, though people who reported changes in sensitivity two to three years later were more likely to show changes in methylation levels.
Future pain therapies may benefit from this changeability. “The potential implication is that, by modulating your lifestyle, you could trigger these switches on or off and modulate your pain threshold,” Bell said. Epigenetic marks may also be reprogrammed pharmaceutically, though not yet with precision, she added.
“Maybe we should be taking more advantage of lifestyle changes, like getting more exercise or social interaction,” Stone said, noting her work finding that injury-induced methylation patterns in mouse brain can be reversed by environmental enrichment (Tajerian et al., 2013). “The body may be a lot smarter than our drugs will ever be at knowing what’s good for it and what isn’t.”
Michele Solis is a science writer and former neuroscientist who lives in Seattle, Washington, US.
Image: Adapted from Bell et al., 2014, Nature Communications.
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