The cancer epigenome

Abstract

PL03-03 Epigenetic silencing of tumor suppressor genes and non-coding RNAs plays a major role in human carcinogenesis. CpG islands, which are frequently located at the transcription start sites of human genes, can become abnormally methylated resulting in heritable silencing. This methylation of cytosine residues is associated with alterations in chromatin structure including the binding of methylated DNA binding proteins and changes in the state of covalent modification of histone residues in nucleosomes. Until now, most of the focus has been on the interplay between covalent histone modifications and DNA cytosine methylation. However, it is becoming increasingly apparent that nucleosomal occupancy plays a substantial role in controlling the accessibility of the promoter to transcriptional factors. We have developed a new assay to examine CpG islands for nucleosomal occupancy and found that several human CpG islands are missing nucleosomes in the regions just upstream of the start sites. Cancer cells with epigenetically silenced promoters showed not only extensive DNA cytosine methylation and deacetylated histones but also have extra nucleosomes in the promoter. Strikingly activation of the silenced promoters by DNA demethylating drugs involves nucleosomal eviction in addition to changes in cytosine methylation and covalent histone modifications. These observations have important implications for epigenetic therapy in which at least three interacting biological processes have to be considered in the silencing and reactivation of promoters by chromatin modifying drugs.