Abstract 4868: Interaction between DNMT3B and polycomb repression complexes and their role in histone modification

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Epigenetic modifications, such as DNA methylation and the histone code, play crucial roles in regulating gene expression during development. Aberrant DNA methylation patterns, characterized by global genomic hypomethylation and gene specific hypermethylation at CpG islands, are found in all cancer cells and contribute directly to tumor development. DNA methyltransferases are responsible for the de novo or heritable maintenance of DNA methylation. DNMT3A and DNMT3B de novo methyltransferases contribute largely to the methylation of retrotransposon sequences and satellite repeats in pericentromeric regions. It is still unclear how gene-specific epigenetic modification patterns are established and maintained in cancer cells. Recently, high-throughput studies reported an overlapping distribution of polycomb repression complexes regulating histone modifications and DNA methyltransferase mediated DNA methylation, suggesting that there are interactions among these epigenetic regulators. Our previous data from DNA methyltransferase knock out cell lines revealed that epigenetic modifiers and the histone code influence the propensity of a gene to become hypermethylated in cancer and that DNMT3B plays an important role in regulating PRC1 function. To gain insight into the mechanisms of how DNMT3B/DNA methylation effects the histone code, and vice versa, we studied the protein-protein interactions between PRC1 components and DNA methyltransferase 3B and their functional consequences. We expressed DNMT3B and each PRC component in both baculovirus and E. coli expression systems. Pull down assays showed that there were multiple interactions between PRC1 components (eg. CBX4 /hPc2) and DNMT3B. Protein-protein interaction domains were further mapped. We then used an in vitro ubiquitination system to study the role of DNMT3B in histone H2A ubiquitination and also studied the effects of these interactions on gene expression in human tumor cell lines. Our results suggest that the interplay between DNMT3B/DNA methylation and PRC1 is important for the function of each protein/complex and that aberrations in these interactions contribute to epigenetic dysregulation in cancer cells. (Supported by NCI grant R01CA114229) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4868.