RING Finger Protein 4 (RNF4) Derepresses Gene Expression from DNA Methylation

Background: RNF4 is a transcription activator, yet the mechanism is unknown. Results: RNF4 mediates ubiquitination and turnover of MeCP2 and thus derepresses transcription from DNA methylation. Conclusion: RNF4 regulates transcription by creating a permissive epigenetic environment. Significance: This study lays the basis for better understanding the role of RNF4 in epigenetics and transcription. RNF4 is an E3 ubiquitin ligase originally identified as a transcription co-activator. The mechanism by which RNF4 promotes transcription remains unclear. In this study, I found that RNF4 antagonizes transcriptional repression mediated by DNA methylation. RNF4 does not promote DNA demethylation, but mediates the ubiquitination of MeCP2, a methyl-CpG-binding domain (MBD) protein. Removal of MeCP2 from gene promoters activates transcription. This study thus not only uncovers how RNF4 functions as a transcription activator, but also reveals the mechanism by which MeCP2 protein stability is regulated.