Growing oocyte-specific transcription-dependent de novo DNA methylation at the imprinted Zrsr1-DMR

Background: Zrsr1 is a paternally expressed imprinted gene located in the first intron of Commdl, and the Zrsr1 promoter resides in a differentially methylated region (DMR) that is maternally methylated in the oocyte. However, a mechanism for the establishment of the methylation has remained obscure. Commdl is transcribed in the opposite direction to Zrsr1 with predominant maternal expression, especially in the adult brain. Results: We found Commedl transcribed through the DMR in the growing oocyte. Zrsr1-DMR methylation was abolished by the prevention of Commdl transcription. Furthermore, methylation did not occur at the artificially unmethylated maternal Zrsr1-DMR during embryonic development when transcription through the DMR was restored in the zygote. Loss of methylation at the maternal Zrsr1-DMR resulted in biallelic Zrsr1 expression and reduced the extent of the predominant maternal expression of Commdl. Conclusions: These results indicate that the establishment of methylation at Zrsr1-DMR occurs in a transcriptiondependent and oocyte-specific manner and caused Zrsr1 imprinting by repressing maternal expression. The predominant maternal expression of Commdl is likely caused by transcriptional interference by paternal Zrsr1 expression.