Abstract
17ß-Estradiol, an epigenetic modulator, is involved in the increased prevalence of migraine in women. Together with the prophylactic efficacy of valproate, which influences DNA methylation and histone modification, this points to the involvement of epigenetic mechanisms. Epigenetic studies are often performed on leukocytes, but it is unclear to what extent methylation is similar in other tissues. Therefore, we investigated methylation of migraine-related genes that might be epigenetically regulated (CGRP-ergic pathway, estrogen receptors, endothelial NOS, as well as MTHFR) in different migraine-related tissues and compared this to methylation in rat as well as human leukocytes. Further, we studied whether 17ß-estradiol has a prominent role in methylation of these genes. Female rats (n = 35) were ovariectomized or sham-operated and treated with 17β-estradiol or placebo. DNA was isolated and methylation was assessed through bisulphite treatment and mass spectrometry. Human methylation data were obtained using the Illumina 450k genome-wide methylation array in 395 female subjects from a population-based cohort study. We showed that methylation of the Crcp, Calcrl, Esr1 and Nos3 genes is tissue-specific and that methylation in leukocytes was not correlated to that in other tissues. Interestingly, the interindividual variation in methylation differed considerably between genes and tissues. Furthermore we showed that methylation in human leukocytes was similar to that in rat leukocytes in our genes of interest, suggesting that rat may be a good model to study human DNA methylation in tissues that are difficult to obtain. In none of the genes a significant effect of estradiol treatment was observed.
Highlights
Migraine is a neurovascular disorder affecting 8–17% of the population [1,2]
Is the rat a valid model for human DNA methylation? We studied whether DNA methylation of human leukocytes in our genes of interest is similar to DNA methylation of rat leukocytes
Overall conclusion In conclusion, our results show that DNA methylation of the rat genes we studied is variable, tissue specific and cannot be extrapolated from leukocytes to other tissues
Summary
Migraine is a neurovascular disorder affecting 8–17% of the population [1,2]. Little is known about the cause of migraine and the prophylactic medication that is used to prevent migraine is only effective in half of the patients [3]. The methylene tetrahydrofolate reductase gene (MTHFR), encoding an important protein of the DNA methylation cycle, has been suggested to be involved in migraine [6,7], genome-wide association studies did not confirm this. They pointed to other genes involved in epigenetic mechanisms [8,9,10]. 17b-estradiol, which seems to be responsible for the 2–3 times higher prevalence of migraine in women compared to men, may exert at least part of its effects via epigenetic mechanisms [12,13].
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