DNA methylation: Biomedical relevance in cancer and development

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Mike Yee

Earth’s islands hold many wonders: beautiful landscapes, unique cultures, flora, fauna, and fascinating case studies of evolutionary history. Zoom in further to the microscopic level of an organism’s genes and there lies another fascinating topographical feature. DNA methylation is an important mechanism of epigenetic regulation, whereby methylation of cytosine bases of DNA is accomplished by DNA methyltransferases (DNMTs). In mammals, this occurs at sites with greater CpG content, also known as CpG islands.

Key early experiments pointed to the role of DNA methylation in regulating cell differentiation and developmental processes. DNA methylation is a complex mechanism, with DNMTs acting as pieces of the chromatin-remodeling complex, and many studies have pointed to the methylation of genes as a mechanism of gene silencing. It is important to note that this is a different mechanism than histone methylation, which is one of the post-translational modifications of the DNA-packaging protein.

A recent article brought to light a strong link between changes at the epigenetic level with DNA methylation and various clinical problems. One of the latest studies involves cancer pathogenicity. Researchers analyzed smoking-associated DNA methylation (SA-DNAm) sites or loci that were identified from 28 previous studies from 2008-2015 that included nine candidate gene-specific methylation (GSM) studies and 19 epigenome-wide association studies (EWAS).

Their methodology included the use of bioinformatic tools that included pathway analyses. They analyzed 320 methylated genes and found that 57 of them correlated with the onset of various cancers. Based on what they found, the authors drew attention to specific pathways, including aryl hydrocarbon receptor signaling pathway, DUSP4, AKT3, MSP-RON signaling (which has a role in regulating macrophages during inflammation), and RAR activation—many of which have been previously shown to have a role in carcinogenesis. These studies are important to consider for further research on the effects of smoking on various aspects of carcinogenesis, including tumor progression, proliferation, cell cycle, and angiogenesis.

Another recent study incorporating a genome-wide approach to researching DNA methylation revealed changes associated with colonic neoplasia. With the use of powerful techniques such as these and the results shown thus far come more questions that include how or what specifically about smoking leads to epigenetic changes such as DNA methylation, and how that then influences functional pathways that may lead to cancer. It is a whole new can of worms, and an all-out search for the smoking gun.

In one of a set of papers recently published in Science, the authors discuss an epigenome-editing tool that is used to insert DNA that is CpG-free into CpG islands to study their effects in pluripotent stem cells (PSCs). This led to methylation of the entire CpG island, and was even maintained throughout differentiating and passaging these PSCs. So this is another powerful tool that can be used to study the role of DNA methylation in stem cell biology and development. The other paper discusses the effect of DNA methylation on the binding of human transcription factors, thus impacting gene regulation.

So, as a scientist who likely takes science home and everywhere else you go, maybe you’ll think about CpG islands the next time you’re on an island-hopping vacation. And feel free to blame me if you do.


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mikecyee

Mike has a Ph.D. in Biomedical Sciences from the University of California, Riverside, a M.S. in Cell and Molecular Biology from San Francisco State University, and a B.A. in English from the University of California, Berkeley.

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