Mechanism of transcriptional silencing mediated by the methyl-CpG binding protein MBD4 and RET finger protein

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Aberrant gene silencing in tumors via methylation of CpG islands in the promoter of many cancer-related genes affects virtually every step in tumor progression. In this process, the methyl-CpG binding domain (MBD) proteins play an essential role in transmitting epigenetic information to downstream regulatory proteins.Among the five MBD proteins identified so far, MBD4 has been the only exception; it has long been thought to be a DNA repair protein. In this study, we demonstrated that MBD4 also has the ability to repress transcription through methyl-CpG sequences. MBD4 is involved in HDAC-dependent repression and directly binds to HDAC1 and corepressor SIN3A. Furthermore MBD4 specifically binds to highly methylated promoters of CDKN2A and MLH1 genes. In order to further investigate the role of MBD4 in methylation-based transcriptional repression, a yeast two-hybrid screening was performed, and the RET finger protein (RFP) was found to be one of the major proteins that interact with the transcriptional repression domain in MBD4. The effect of the MBD4-mediated transcriptional repression in methylated CDKIV2A and MLH1 promoters was extremely enhanced by the overexpression of RFP. Because RFP has been detected at high levels in a variety of tumor cell lines as well as testis, and embryos, RFP may have an important role in the enhancement of transcriptional repression through MBD proteins in tumorigenesis, spermatogenesis, and embryogenesis.