title: Methylation of migraine-related genes in different tissues of the rat.
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.
authors.affiliation: Dept. of Internal Medicine, Div. of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Sieneke
authors.initials: S
authors.lastname: Labruijere
authors.affiliation: Dept. of Internal Medicine, Genetics Laboratory, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Stolk
authors.affiliation: Dept. of Internal Medicine, Genetics Laboratory, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Michael
authors.initials: M
authors.lastname: Verbiest
authors.affiliation: Dept. of Internal Medicine, Div. of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.affiliation: Dept. of Internal Medicine, Div. of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.affiliation: Dept. of Biostatistics, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Paul H C
authors.initials: PH
authors.lastname: Eilers
authors.affiliation: Dept. of Internal Medicine, Div. of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: A H Jan
authors.initials: AH
authors.lastname: Danser
authors.affiliation: Dept. of Internal Medicine, Genetics Laboratory, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: Dept. of Internal Medicine, Div. of Pharmacology, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Antoinette
authors.initials: A
authors.lastname: MaassenVanDenBrink
mesh_terms: D000818:Animals; D058286:Calcitonin Receptor-Like Protein / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008881:Migraine Disorders / Q000235:genetics*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D010052:Ovariectomy; D051381:Rats; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics
chemical_list: C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D018015:Receptors, Calcitonin Gene-Related Peptide; D011960:Receptors, Estrogen; D004958:Estradiol; D052250:Nitric Oxide Synthase Type III