Mouse Peg3 encodes a DNA-binding protein involved in the milk letdown process. In the current study, we tested whether PEG3 controls the expression of the oxytocin receptor gene. According to the results, PEG3 directly binds to a genomic region within the 3rd exon of Oxtr, which contains a DNA-binding motif for PEG3. In nursing female mice, removal of PEG3 resulted in the increased expression of Oxtr in mammary epithelial cells and also in the hypothalamus. This suggests a repressor role of PEG3 in the expression of Oxtr in these tissues. Overall, this study suggests that Peg3 may function as a direct transcriptional regulator for Oxtr expression that acts to moderate the milk letdown process.

Initial bioinformatic analyses suggested that some iHMRs may be noncanonical enhancers for imprinted genes. Consistent with this, Peg3- and H19-iHMRs showed context-dependent promoter and enhancer activity. Further, deletion of Peg3-iHMR resulted in allele- and sex-specific misregulation of several imprinted genes within the domain. Taken together, these results suggest that some iHMRs may function as domain-wide regulators for the associated imprinted domains.