Cancer epigenomics: DNA methylomes and histone-modification maps

Key Points

  • During the past two decades, an increasing amount of experimental data has been gathered that support the idea that epigenetic alterations, particularly DNA methylation and histone modifications, have a crucial role in the development and progression of human cancer.

  • The epigenetic silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation has emerged as a driving force in tumorigenesis. Further investigations are required to understand the contributions of genomic DNA hypomethylation and altered histone-modification signatures in human tumours.

  • Epigenetic research is moving on from candidate-gene approaches towards genome-wide analyses, on the basis of the combination of new techniques combining bisulphite treatment and PCR, new antibodies against epigenetic marks and the epigenetic machinery, and high-resolution microarray platforms.

  • These new epigenomic analyses show a profound disruption of the epigenetic modifications of cancer cells, with a large number of genes undergoing methylation-associated silencing, a global change in the acetylation and methylation profiles of histones, and aberrations in the genes responsible for the maintenance of normal chromatin structure.

  • Epigenomic technologies have promising translational applications for human cancer, with potential for early diagnosis, prognosis and clinical management, particularly in the young field of pharmacoepigenetics.

  • Our knowledge of cancer epigenetics will benefit greatly from the development of ambitious whole-genome endeavours, such as the international consortia that have been set up for the analysis of complete human and model-organism epigenomes.

Abstract

An altered pattern of epigenetic modifications is central to many common human diseases, including cancer. Many studies have explored the mosaic patterns of DNA methylation and histone modification in cancer cells on a gene-by-gene basis; among their results has been the seminal finding of transcriptional silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation. However, recent technological advances are now allowing cancer epigenetics to be studied genome-wide — an approach that has already begun to provide both biological insight and new avenues for translational research. It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches.

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Figure 1: Altered DNA-methylation patterns in tumorigenesis.
Figure 2: Techniques for studying epigenetic changes in cancer.
Figure 3: Methods for profiling genome-wide DNA-methylation patterns.
Figure 4: Histone-modification maps for a typical chromosome in normal and cancer cells.

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Acknowledgements

M.E. research is supported by the Science Department of the Spanish Government.

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FURTHER INFORMATION

Cancer Epigenetics homepage

Epigenetics Society

Epigenome Network of Excellence

Human Epigenome Project

Manel Esteller's Laboratory

Glossary

Endoparasitic sequences

Repeated sequences, most of which are derived from transposable elements. These sequences are propagated by inserting new copies of themselves into random sites in the genome.

Genomic imprinting

The epigenetic marking of a locus on the basis of parental origin, which results in monoallelic gene expression.

High-performance liquid chromatography

(HPLC). A technique for separating DNA or protein molecules by molecular weight and conformation. The molecules are resolved by differences in their distribution between a stationary phase and a mobile phase. The resolution is increased by increasing the pressure of the system.

High-performance capillary electrophoresis

(HPCE). A class of separation techniques that use narrow-bore fused-silica capillaries to separate a complex mixture of chemical compounds. Molecules are separated on the basis of differences in charge, size, structure and hydrophobic potential using strong electric fields.

Methylation-specific PCR

This DNA-methylation assay entails initial modification of DNA by sodium bisulphite, converting all unmethylated, but not methylated, cytosines to uracil, and subsequent amplification with primers that are specific for methylated versus unmethylated DNA.

Two-dimensional electrophoresis

A gel electrophoresis method in which the proteins in a sample are separated by their isoelectric points in one dimension, and by size in a second, perpendicular dimension.

MethyLight

A high-throughput quantitative methylation assay that uses fluorescence-based real-time PCR (TaqMan) technology and requires no further manipulations after the PCR step. This technique is carried out in combination with bisulphite treatment (in which unmethylated cytosine residues are converted to uracil), and sequence discrimination is achieved by designing the primers to overlap with potential sites of DNA methylation (CpG dinucleotides).

Pyrosequencing

A DNA-sequencing method in which light is emitted as a result of an enzymatic reaction, each time a nucleotide is incorporated into the growing DNA chain. As applied to methylation detection, methylation-dependent DNA sequence variation, which is achieved by sodium bisulphite treatment, is treated as a kind of SNP of the C–T type, and is subjected to conventional SNP typing.

Arbitrary primed PCR

Amplification of genomic DNA using arbitrary primers. The first amplification cycles are carried out at a low annealing temperature, such that the primer hybridizes to many non-specific sequences. The temperature is then increased, so that only the 'best' products of the initial annealing events are amplified further, generating a number of discrete bands that provide a fingerprint of the genome.

Amplification of intermethylated sites

(AIMS). A DNA-methylation fingerprinting technique that uses methyl-isoschizomers and arbitrary PCR amplification to obtain many anonymous bands, which represent DNA sequences flanked by two methylated sites.

Chromatin immunoprecipitation

(ChIP). The isolation, using specific antibodies, of chromatin fragments that are bound by a particular nuclear factor or associated with a particular histone-modification signature. The immunoprecipated DNA can subsequently be analysed with specific PCR primers.

ChIP-on-chip

A combination of chromatin immunoprecipitation with hybridization to genomic microarrays that is used to identify DNA sequences bound to a particular nuclear factor or with a specific histone-modification profile.

Methyl-DIP

(Methylated DNA immunoprecipitation).Immunoprecipitation with anti-5-methylcytosine antibodies followed by hybridization to genomic microarrays, allowing the identification of methyl-CpG-rich sequences.

Tiling microarrays

Microarrays that contain a set of overlapping oligonucleotides or other probes that span either the entire genome or, for a more specialized approach, a subregion of interest.

Mass spectrometry

An analytical technique determining molecular mass. This involves an ion source in which gas-phase molecular ions are produced from the analyte molecules, a mass analyser in which electrical and/or magnetic fields are used to separate the analyte ions by their different mass-to-charge ratios, and a detector for recording the separated ions.

Liquid chromatography–electrospray mass spectrometry

A mass spectrometry technique in which ionization of molecules is carried out within aerosols of small droplets. Molecules are then identified using electric and magnetic fields.

Tandem mass spectrometry

An analytical system in which two linked mass spectrometers are used to measure small amounts of metabolites. The analytes are separated according to their mass and charge. By programming the instrument to respond to only certain masses, a high degree of specificity and sensitivity can be achieved.

Adenoma

A cellular growth of glandular origin, which can arise from organs including the colon and the adrenal, pituitary and thyroid glands. These growths are benign, but some are known to have the potential, over time, to transform to malignancy (at which point they become known as adenocarcinoma.)

Prognostic dendogram

A tree diagram that represents the relative similarities among different samples corresponding to human patients in terms of outcome prediction. Samples clustering in the same branch of the dendrogram have the same prognostic markers (for example, age, stage, chromosomal deletions or gains, or specific gene expression) and are likely to have the same outcome.

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Esteller, M. Cancer epigenomics: DNA methylomes and histone-modification maps. Nat Rev Genet 8, 286–298 (2007). https://doi.org/10.1038/nrg2005

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