Aberrant DNA Methylation and Histone Modifications in Cancer

Abstract

DNA (deoxyribonucleic acid) methylation of cytosines in CpG dinucleotides and post‐translational modifications of histone amino acids are epigenetic mechanisms that are in normal cells involved in specific cell functions, particularly in regulation of transcription and maintenance of stable chromatin. The epigenetic code is highly dynamic and enables the cells to regulate their responses to the intrinsic or environmental signals. Aberrations of DNA methylation patterns and histone modifications are major features observed in all types of cancer. Integrated research of genomic alterations, erroneous gene expression and modifications of epigenomes in cancer cells has revealed the complexity and heterogeneity of this disease. Some of the novel therapeutic and diagnostic approaches based on aberrant promoter hypermethylation and histone modifications, particularly acetylation, have already been translated into a clinical setting, whereas a number of others are being examined in clinical trials.

Key Concepts

  • DNA methylation and histone modifications cooperate in regulation of certain cell functions and responses.
  • Cancer development and progression are characterised by diverse aberrations in epigenetic profiles.
  • Changes in DNA methylation profiles could be used to define specific subsets of cancers, which harbour characteristic genetic alterations.
  • Hypermethylation or hypomethylation of gene promoters, resulting in silencing or activating the gene transcription, respectively, are fundamental in the identification of novel tumour suppressors and oncogenes.
  • Unravelling the functional consequences of methylation signature in nonpromoter regions is complex and will require further research efforts to discern their role in healthy and diseased cells.
  • Epigenetic profiling of cancers has already identified and is still identifying novel targets for the development of therapeutic and diagnostic approaches.

Keywords: biomarker; cancer; CpG island; chromatin; epigenetic therapy; gene silencing; epigenetics; gene expression regulation; histone modifications

Figure 1. Schematic presentation of major DNA methylation and demethylation pathways in mammals. DNA methylation at the carbon‐5 position of cytosine (C, ∼20% of all bases) in the dinucleotide CpG is catalysed by DNMTs to yield 5‐methylcytosine (5mC, ∼1% of all bases and ∼60% of all CpGs) by transferring the methyl group from S‐adenosylmethionine (SAM) to cytosine. TET enzymes are implicated in conversions of 5mC, first by catalysing oxidization of 5mC to 5‐hydroxymethylcytosine (5hmC, ∼0.1% of all bases), followed by formation of 5‐formylcytosine (5fC) and 5‐carboxylcytosine (5caC) (together, oxi‐mC). Through these oxidations, TET proteins mediate active demethylation of methylated CpGs. 5hmC, 5fC and 5caC are repaired via thymine DNA glycosylase (TDG)‐mediated base excision repair (BER) of 5fC:G and 5caC:G base pairs. In addition, replication‐dependent passive demethylation can also occur. Reproduced from Huang and Rao 2014 © Elsevier.
Figure 2. Schematic representation of histone modifications. + Indicates modifications associated with active transcription, − indicates modifications that repress transcription, ac, acetylation; me, methylation; ub, ubiquitination; me1, monomethylation; me2, demethylation; s, symmetric covalent modification.
Figure 3. An example of DNA methylation patterns in normal and cancer cells. (a) For example, in normal cells, most CpGs located outside of promoters in gene bodies and intergenic regions are methylated (red circles), whereas promoter‐associated CpG islands are protected from DNA methylation (white circles). (b) In cancer cells, loss of 5‐methylcytosine occurs at gene bodies and intergenic regions, whereas CpG‐rich regions like promoters are usually heavily methylated, which might lead to transcriptional repression. CpG shores, which have intermediate densities of CpG dinucleotides, are associated with tissue‐specific methylation. In bottom plots, global loss (left plot) and focal gain (right plot) of DNA methylation of two genes, the deleted in colon cancer gene (DCC) and glutathione S‐transferase P1 gene (GTSP1), are presented. Below the gene track are tracks for CpG islands and selected histone modifications, including H3K4me3, which is associated with transcriptionally active promoters, and H3K4me1 and H3K27ac as markers for enhancers. Each colour of the histone tracks represents an individual ENCODE cell line. DCC was taken as an exemplary locus for which long‐range hypomethylation regions (horizontal blue bars) are observed in the breast cancer cell line HCC1954 and in the liver carcinoma cell line HepG2, but not in normal mammary epithelial cells (HMEC) or the myofibroblast cell line IMR90. GTSP1 represents an example of promoter hypermethylation (highlighted in red) in cancer cell lines compared to normal cells. The data was obtained from the University of California Santa Cruz (USCS) genome browser (https://genome.ucsc.edu/). Reproduced with permission form Witte et al. 2014 © BioMed Central.
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Further Reading

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Web Links

A database of clinical trials, https://clinicaltrials.gov/

A database of DNA methylation and gene expression in human cancer, http://methhc.mbc.nctu.edu.tw/

HIstome: The Histone Infobase, http://www.actrec.gov.in/histome/index.php

The Cancer Genome Atlas (TCGA) Research Network, http://cancergenome.nih.gov/

The Encyclopedia of DNA Elements (ENCODE) Consortium project, http://www.ensembl.org/info/website/tutorials/encode.html and https://www.encodeproject.org/

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Hudler, Petra(Jul 2016) Aberrant DNA Methylation and Histone Modifications in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0026336]