title: Brain region-specific methylation in the promoter of the murine oxytocin receptor gene is involved in its expression regulation.
abstract: Oxytocin is a nine amino acid neuropeptide that is known to play a critical role in fetal expulsion and breast-feeding, and has been recently implicated in mammalian social behavior. The actions of both central and peripheral oxytocin are mediated through the oxytocin receptor (Oxtr), which is encoded by a single gene. In contrast to the highly conserved expression of oxytocin in specific hypothalamic nuclei, the expression of its receptor in the brain is highly diverse among different mammalian species or even within individuals of the same species. The diversity in the pattern of brain Oxtr expression among mammals is thought to contribute to the broad range of social systems and organizations. Yet, the mechanisms underlying this diversity are poorly understood. DNA methylation is a major epigenetic mechanism that regulates gene transcription, and has been linked to reduced expression levels of the Oxtr in individuals with autism. Here we hypothesize that DNA methylation is involved in the expression regulation of Oxtr in the mouse brain. By combining bisulfite DNA conversion and Next-Generation Sequencing we found that specific CpG sites are differentially methylated between distinct brain regions expressing different levels of Oxtr mRNA. Some of these CpG sites are located within putative binding sites of transcription factors known to regulate Oxtr expression, including estrogen receptor α (ERα) and SP1. Specifically, methylation of the SP1 site was found to positively correlate with Oxtr expression. Furthermore, we revealed that the methylation levels of these sites in the various brain regions predict the relationship between ERα and Oxtr mRNA levels. Collectively, our results suggest that brain region-specific expression of the mouse Oxtr gene is epigenetically regulated by DNA methylation of its promoter.
authors.affiliation: Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel.
authors.forename: Hala
authors.initials: H
authors.lastname: Harony-Nicolas
authors.affiliation: Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel.
authors.forename: Shimrat
authors.initials: S
authors.lastname: Mamrut
authors.affiliation: Tauber Bioinformatics Research Center and Department of Evolutionary & Environmental Biology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel.
authors.forename: Leonid
authors.initials: L
authors.lastname: Brodsky
authors.affiliation: Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel.
authors.forename: Hadar
authors.initials: H
authors.lastname: Shahar-Gold
authors.affiliation: Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel.
authors.forename: Liza
authors.initials: L
authors.lastname: Barki-Harrington
authors.affiliation: Department of Neurobiology, Faculty of Natural Sciences, University of Haifa, Haifa 31905, Israel. Electronic address: shlomow@research.haifa.ac.il.
authors.forename: Shlomo
authors.initials: S
authors.lastname: Wagner
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018045:Receptors, Oxytocin / Q000235:genetics* / Q000378:metabolism
chemical_list: D047628:Estrogen Receptor alpha; C576074:OXTR protein, mouse; D012333:RNA, Messenger; D018045:Receptors, Oxytocin
keywords: Bioinformatics; Brain; DNA methylation; Epigenetics; Oxytocin receptor; Transcription regulation