Abstract 4442: Very low methylation is a novel epigenetic regulatory mechanism in normal tissues and predisposes to hypermethylation in cancer

Abstract

Abstract High level DNA methylation of promoter CpG Island (CGI) represses gene expression. However, low-level CGI methylation is usually not distinguished from complete absence of methylation. Here we show that Very Low Methylated Regions (VLMRs 1-20%) on promoter CGIs are present in up to 20% of human and mouse genes and negatively correlate with gene expression in all tissues examined. In vitro, low-level methylation directly represses reporter gene expression; an effect mediated by methyl-CpG-binding proteins as transient knockdown of MBD4 reverses this repression. In vivo VLMR genes are enriched for polycomb occupancy but can also occur in H3K4me3 occupied promoters, where it correlates with gene repression independent of polycomb complex binding. VLMRs in promoter CGIs in healthy WBCs are 19 fold and 65 fold more likely to gain hypermethylation in Acute Myelogenous Leukemia and Myelodysplastic Syndrome patients respectively compared to unmethylated CGIs (<1%). Our study reveals a novel epigenetic control mechanism that has strong effects on gene expression in normal tissues and accounts for most of the gene specificity of hypermethylation in cancer. Citation Format: priyanka madireddi, Jaroslav Jelinek, Justin Lee, Takahiro Sato, Jean-Pierre Issa. Very low methylation is a novel epigenetic regulatory mechanism in normal tissues and predisposes to hypermethylation in cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4442.