DNA hypermethylation in disease: mechanisms and clinical relevance

Abstract

Increasing numbers of studies implicate abnormal DNA methylation in cancer and many non-malignant diseases. This is consistent with numerous findings about differentiation-associated changes in DNA methylation at promoters, enhancers, gene bodies, and sites that control higher-order chromatin structure. Abnormal increases or decreases in DNA methylation contribute to or are markers for cancer formation and tumour progression. Aberrant DNA methylation is also associated with neurological diseases, immunological diseases, atherosclerosis, and osteoporosis. In this review, I discuss DNA hypermethylation in disease and its interrelationships with normal development as well as proposed mechanisms for the origin of and pathogenic consequences of disease-associated hypermethylation. Disease-linked DNA hypermethylation can help drive oncogenesis partly by its effects on cancer stem cells and by the CpG island methylator phenotype (CIMP); atherosclerosis by disease-related cell transdifferentiation; autoimmune and neurological diseases through abnormal perturbations of cell memory; and diverse age-associated diseases by age-related accumulation of epigenetic alterations.

Keywords: CpG island methylator phenotype (CIMP); DNA hypermethylation; DNMT; TET; aging; atherosclerosis; brain disease; cancer stem cells; immune dysfunction; osteoporosis.

Figure 1.

Developmental or disease-associated DNA hypermethylation can modulate gene expression in various ways. (a) and (b), down-regulation of gene expression by DNA hypermethylation (either initiating or stabilizing gene repression). (c) and (d), positive associations of DNA hypermethylation with gene expression. (e) and (g), positive or negative associations with gene expression. (f), effects on the nature of the transcript (RNA isoform), which can occur without changes the steady-state levels of the transcript.

Figure 2.

Illustration of cancer-associated promoter hypermethylation and tissue-specific enhancer hypomethylation that correlate with expression. (a) Isoforms of the DKK3 tumour suppressor gene, which encodes a repressor of Wnt signalling (chr11:11,981,590–12,036,438, hg19, as seen in the UCSC genome browser [84]). Broken arrow, TSS; tall blue boxes, coding exons; short boxes, 5ʹ or 3ʹ non-coding exonic regions. (b) CpG density and the one CpG island (CGI) in this region. (c) DNA methylation levels from WGBS (gold bars) and regions of significantly low DNA methylation relative to the rest of the same genome (horizontal blue bars [83]). (d) Publicly available genome-wide mapping of 5hmC in prefrontal cortex (PFC), as determined by TET-assisted bisulfite sequencing [11]. (e) Predicted features of chromatin segments determined from histone modifications [1]. Str, Wk, Biv Promoter and Str, Wk, Biv Enhancer, chromatin with the histone marks characteristic of strong (active), weak, or bivalent (poised) promoters or enhancers. Enh/Prom, chromatin with histone modifications found in both active promoters and enhancers; Txn-chrom, chromatin with the histone modification of genes actively involved in transcription; Low signal, chromatin with little or no H3 lysine-4, 9, or 27 modifications; Repr, chromatin with repressive H3 lysine-27 trimethylation. (f) RNA-seq for two cell cultures (malignant, MCF-7, vs. non-malignant breast cancer epithelial cells, HMEC) and for tissues (bar graph for median values from hundreds of normal samples [110]). Orange lettering, cancer tissues or cell lines; PBMC, peripheral blood mononuclear cells; HMEC, human mammary epithelial cell cultures (untransformed); TPM, transcripts per million.