DNA methylation of specific CpG sites in the promoter region regulates the transcription of the mouse oxytocin receptor

PLoS One. 2013;8(2):e56869. doi: 10.1371/journal.pone.0056869. Epub 2013 Feb 18.

Abstract

Oxytocin is a peptide hormone, well known for its role in labor and suckling, and most recently for its involvement in mammalian social behavior. All central and peripheral actions of oxytocin are mediated through the oxytocin receptor, which is the product of a single gene. Transcription of the oxytocin receptor is subject to regulation by gonadal steroid hormones, and is profoundly elevated in the uterus and mammary glands during parturition. DNA methylation is a major epigenetic mechanism that regulates gene transcription, and has been linked to reduced expression of the oxytocin receptor in individuals with autism. Here, we hypothesized that transcription of the mouse oxytocin receptor is regulated by DNA methylation of specific sites in its promoter, in a tissue-specific manner. Hypothalamus-derived GT1-7, and mammary-derived 4T1 murine cell lines displayed negative correlations between oxytocin receptor transcription and methylation of the gene promoter, and demethylation caused a significant enhancement of oxytocin receptor transcription in 4T1 cells. Using a reporter gene assay, we showed that methylation of specific sites in the gene promoter, including an estrogen response element, significantly inhibits transcription. Furthermore, methylation of the oxytocin receptor promoter was found to be differentially correlated with oxytocin receptor expression in mammary glands and the uterus of virgin and post-partum mice, suggesting that it plays a distinct role in oxytocin receptor transcription among tissues and under different physiological conditions. Together, these results support the hypothesis that the expression of the mouse oxytocin receptor gene is epigenetically regulated by DNA methylation of its promoter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Line
  • CpG Islands*
  • DNA Methylation*
  • Epigenesis, Genetic
  • Female
  • Gene Expression Regulation
  • Gene Order
  • Genes, Reporter
  • Mice
  • Molecular Sequence Data
  • Promoter Regions, Genetic*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Oxytocin / genetics*
  • Transcription, Genetic*

Substances

  • RNA, Messenger
  • Receptors, Oxytocin

Grant support

This research was supported by the Legacy Heritage Bio-Medical Program of the Israel Science Foundation (grant #1901/08 to SW and LBH) and by the Autism Speaks Foundation (grant #3613 to SW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.