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.
Highlights
Oxytocin (OT) is a nonapeptide, mostly known for its role in enhancing contractions of the uterus during labor and mediating milk release from mammary glands during suckling [1]
We focused our analysis of DNA methylation on a,400 bp region within the promoter, which contains seven CpG sites
We used two mouse-derived cells lines, the GnRH-releasing GT1-7 immortalized neurons, and the mammary gland-derived 4T1 carcinoma cells to show that DNA methylation has an inhibitory effect on Oxtr transcription
Summary
Oxytocin (OT) is a nonapeptide, mostly known for its role in enhancing contractions of the uterus during labor and mediating milk release from mammary glands during suckling [1]. Transcription of the rodent Oxtrwas studied in brain and peripheral tissues where it was found to be partly regulated by estrogens [10,11,12,13,14]. In parallel to the estrogen levels, Oxtr peaks in both the uterus and mammary glands before and during labor. The mechanism by which estrogen regulates Oxtr transcription is elusive, partly because the Oxtr promoter of several mammalian species, including that of humans, lacks a palindromic estrogen response element (ERE) [1,4,5,6,19]. While Oxtr expression can be upregulated by estrogen in tissues, multiple attempts to obtain a similar effect in cultured cells were unsuccessful [12]
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