A decade of exploring the cancer epigenome - biological and translational implications

Abstract

The past decade has highlighted the central role of epigenetic processes in cancer causation, progression and treatment. Next-generation sequencing is providing a window for visualizing the human epigenome and how it is altered in cancer. This view provides many surprises, including linking epigenetic abnormalities to mutations in genes that control DNA methylation, the packaging and the function of DNA in chromatin, and metabolism. Epigenetic alterations are leading candidates for the development of specific markers for cancer detection, diagnosis and prognosis. The enzymatic processes that control the epigenome present new opportunities for deriving therapeutic strategies designed to reverse transcriptional abnormalities that are inherent to the cancer epigenome.

Conflict of interest statement

Competing interests statement

The authors declare competing financial interests. See Web version for details.

Figures

Figure 1. Model of the overall structure of the epigenome in normal human cells

This diagram shows the balanced state of chromatin, nucleosome positioning and DNA methylation, which maintains the normal packaging state of DNA. A silenced gene (indicated by a red X over the transcription start site designated by the arrow) at the top of the figure has its promoter CpG island occupied by a Polycomb group (PcG) complex (indicated by a red shaded area) that mediates chromatin changes that include the repressive histone modification trimethylation of lysine 27 on histone 3 (H3K27me3). There is no CpG DNA methylation within the gene promoter CpG island (shown by pale blue circles) and nucleosomes are positioned over the transcription start site. Sites upstream from the promoter are heavily DNA methylated (shown by red circles). The gene promoter illustrated below the silenced gene has been signalled to adopt a fully active transcription state and retains the active H3K4me3 marks at the promoter. It also has acetylation of key H3 and H4 lysines, the presence of the variant histone, H2A.Z (not shown) and H3K36me3 in the gene body to facilitate transcriptional elongation. The transcription start region (indicated by an arrow) is not occupied by nucleosomes. Just below, a distal enhancer is shown for this gene with an active nucleosome configuration, and the signature histone modification for enhancers, H3K4me1, is present. Finally, towards the bottom of the figure, the packaging of the majority of the cellular DNA into a transcriptionally repressed configuration is depicted, with compacted nucleosomes, the presence of H3K9me2 and H2K9me3, which are signature repressive marks for constitutive heterochromatin, the presence of heterochromatin protein 1 (HP1; also known as CBX5) and extensive DNA methylation. The folding of the heterochromatin into chromosomal locations in the nucleus is shown. Image is adapted, with permission, from REF. © (2008) Macmillan Publishers Ltd. All rights reserved.

Figure 2. The cancer epigenome and relevant gene mutations

The cancer epigenome is characterized by simultaneous global losses in DNA methylation (indicated by pale blue circles) with hundreds of genes that have abnormal gains of DNA methylation (indicated by red circles) and repressive histone modifications (indicated by red flags) in promoter region CpG islands. The hypomethylated regions have an abnormally open nucleosome configuration and abnormally acetylated histone lysines (indicated by green flags). Conversely, abnormal DNA hypermethylation in promoter CpG islands is associated with nucleosomes positioned over the transcription start sites of the associated silenced genes (indicated by an arrow with a red X). Recent whole-exon sequencing of human cancers has shown a high proportion of mutations in genes in leukaemias, lymphomas, and ovarian, renal and pancreatic cancers, and rhabdomyosarcoma–,– (indicated in yellow boxes), which are depicted as helping to mediate either abnormal DNA methylation, histone modifications and/or nucleosome remodelling,,,,,–. ARID1A, AT-rich interactive domain-containing protein 1A; DNMT3A, DNA methyltransferase 3A; EZH2, ehancer of zeste 2; IDH1, isocitrate dehydrogenase 1; MLL, mixed lineage leukaemia; PBRM1, protein polybromo 1; SNF5, SWI/SNF-related, matrix associated, actin-dependent regulator of chromatin, subfamily B, member 1; VHL, Von Hippel–Lindau.

Figure 3. Modes of abnormal gene silencing in cancer

The currently suggested routes to abnormally silenced genes in cancer are shown. Genes that are active in cells throughout development and adult cell renewal initially have active promoter chromatin that is characterized by the presence of the histone modification, H3K4me (indicated by green circles and dashed arrows), and a lack of DNA methylation (indicated by pale blue circles). Genes that become silenced (indicated by a red X) can do so either by the acquisition of DNA methylation (indicated by red circles) and the presence of the repressive mark, H3K9me (indicated by orange circles and black arrows), or by the presence of Polycomb-mediated repressive chromatin (PRC) marks, H3K27me (purple circles and grey arrows). DNA methylation and H3K9me marks during tumour progression are shown. The wide yellow arrows at the sides of the figure depict movements that link stem and progenitor cells and differentiated cells and which can be impeded by epigenetic abnormalities in cancer or which can be corrected by epigenetic therapy.

Timeline. Example of key advances in epigenetics and cancer over the past decade