Role of DNA Methylation in Disease

DNA methylation plays key roles in gene expression and regulation. It is an epigenetic signaling tool that locks genes in the “off position” and is an important component in various cellular processes such as genomic imprinting, embryonic development, maintenance of chromosome stability, and X-chromosome inactivation. Scientists have linked abnormal methylation to various devastating outcomes, including human diseases.

DNA methylation involves the addition of a methyl group to the 5-carbon of the cytosine ring, which results in 5-methylcytosine or 5-mC. These methyl groups inhibit transcription by occupying the DNA’s major groove. 5-mC constitutes about 1.5% of genomic DNA.

Regulation of DNA methylation by methyltransferases

DNA methylation is catalyzed by DNA methyltransferases (DNMTs) and is controlled at many different points in cellular processes. Three types of DNMTs, namely, DNMT1, DNMT3a, and DNMT3b are needed to establish and maintain DNA methylation patterns.

DNMT1 seems to be involved in the maintenance of DNA methylation patterns that are already established, while DNMT3a and DNMT3b seem to be involved in the establishment of new DNA methylation patterns. In the case of diseases such as cancer, this may be different, in that both DNMT1 and DNMT3b may be involved in maintaining hypermethylation in cancer cells.

DNA methylation epigentics

DNA methylation is a reversible epigenetic modification. The removal of a methyl group or demethylation is needed to reprogram genes and is therefore also important in mechanisms of disease such as tumor growth. Demethylation is catalyzed by enzymes called DNA demethylases.

Significance of DNA methylation

The role of DNA methylation in gene expression varies across different kingdoms of organisms. 5'—C—phosphate—G—3' (CpG) methylation is distributed fairly globally in mammals, whereas among invertebrates, the methylation pattern is generally "mosaic," with heavily methylated DNA regions being interspersed with regions that are not methylated.

In mammals, the global methylation pattern makes it challenging to determine whether methylation is a default state or in fact targeted to specific sequences of genes. However, the CpG islands usually occur close to transcription start sites, suggesting that there is a system for recognition.

In plants, as much as 50% of cytosine residues are in a methylated state, while in fungi, only repeated sequences of DNA are methylated, with methylation completely absent in some species.

The significance of 5-mC as a key epigenetic modification in gene expression is widely recognized. For instance, a decrease in global DNA methylation or DNA hypomethylation is likely to be the result of methyl deficiency caused by various environmental factors and it has been suggested as a molecular marker in many biological processes, including cancer.

Determining the 5-mC content or global methylation in cells that have been impacted by environmental factors or become diseased, could offer information to aid disease detection and analysis. Moreover, the presence of 5-fC, the intermediate of DNA demethylation, in tissues and cells may serve as a marker for active DNA demethylation.

DNA methylation and disease

Since DNA methylation plays such an important role in gene expression, it seems obvious that faulty methylation could have devastating consequences, including human disease.

Researchers have conducted many studies examining the association between errors in this methylation and diseases such as cancer, muscular dystrophy, lupus, and various birth defects. This is hoped to provide valuable insights to improve the understanding, treatment, and prevention of these disorders.

Studies have focused on the connection between DNA methylation and tumor suppressor genes and cancer. DNA hypermethylation has been shown to silence tumor suppressor genes in cancer cells.

By contrast, cancer cell genomes have exhibited hypomethylation overall in comparison to healthy cells, but with hypermethylation of the genes involved in tumor cell invasion, DNA repair, regulation of the cell cycle and other processes where silencing leads to metastasis.

The detection of hypermethylation in some cancers such as colon cancer is possible early on in the course of disease and may serve as a valuable biomarker for the condition.

Reviewed by Sally Robertson, BSc



Further Reading

Last Updated: Feb 2, 2017


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