Authors: Ksenia Skvortsova1, Etienne Masle-Farquhar2, Phuc Loi Luu1, Jenny Z. Song1, Wenjia Qu1, Elena Zotenko1, Timothy Peters2, Joanne Reed2, Christopher Goodnow2,3, Clare Stirzaker1,3 and Susan J. Clark1,3
Affiliations: 1Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, Australia; ; 2Immunology Division, Garvan Institute of Medical Research, Sydney, Australia.; 3St Vincent's Clinical School, UNSW Sydney, Sydney, Australia.
Abstract :
DNA methylation plays a key role in demarcation of regulatory regions, including promoter-associated CpG islands. While CpG islands are typically maintained in an unmethylated state, a proportion of islands are subject to hypermethylation in cancer cells. A widely studied, but still unresolved question to date, is to understand what triggers the aberrant changes to the DNA methylation landscape in cancer. Using WGBS we have identified hypermethylated CpG islands in prostate and breast cancer, including a subset of CpG islands that display a novel mode of DNA methylation encroachment across 5’ or 3’ CpG island borders, resulting in smaller islands and new discreet CpG island borders. By intergrating whole-genome bisulphite sequencing and ChiP-seq data, we have revealed that the pattern of H3K4 monomethylated nucleosomes in embryonic stem cells and normal prostate epithelial cells, determines the mode of aberrant hypermethylation in cancer, including the novel mode of DNA methylation encroachment across the borders of CpG islands. Notably, we show that genetic manipulation of KMT2D results in depletion of H3K4me1 and loss of DNA methylation at the CpG island borders, and, conversely enrichment of H3K4me1 results in a gain CpG island border hypermethylation (Skvortsova et al Cancer Cell accepted) . Together these findings identify a unique role for H3K4me1 in shaping CpG island methylation in normal and cancer cells.