Structure and function of a imprinting center in the region of human SNRPN gene

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Certain mammalian genes are expressed exclusively from either the paternal and the maternal chromosome because of a differential marking process that occurs during gametogenesis. This epigenetic marking is called genomic imprinting. I focused on an imprinted SNRPN gene region in the Prader-Willi/Angelman syndrome. Our data revealed the correlations between the differential SNRPN gene activity and the changes in DNA methylation, higher order chromatin structure and replication timing. Further, we isolated and characterized a new member of the methyl-CpG binding proteins, named PCM1 (MBD1), which possesses a methyl-CpG binding domain and cysteine-rich CXXC regions. Four PCM1 isoforms were newly identified to be alternatively spliced in the CXXC domains and the C-terminus. All forms of PCM1 inhibited the promoter activity of SNRPN gene via methylation. Interestingly, three copies of the CXXC domain in the PCM1 isoforms enhanced the suppressive effect on the transcription from both methylated and unmethylated SNRPN promoters. In contrast, PCM1 isoforms containing two copies of the CXXC domain inhibited methylated but not unmethylated promoter, suggesting that the CXXC domain is a regulatory element of PCMI.These findings suggested that methyl-CpG binding proteins play important roles in methylation-mediated transcriptional silencing of SNRPN gene.