DNA Methylation and 5-methylcytosine

One of the most important and well-characterized epigenetic mechanisms is methylation of cytosine (C) to produce 5-methylcytosine (5mC), often called "the 5th base".

What does cytosine methylation do?

When 5mC is generated in the regulatory regions of genes, it recruits proteins that condense the surrounding chromatin and stably suppress gene expression. This mechanism plays an important role in development and disease pathogenesis.

What kind of diseases?

DNA methylation plays a key role in multiple diseases - below are some of the key observations made in three of them: Type 2 Diabetes, Glioblastoma and Alzheimer's disease.

Type 2 Diabetes is regulated by methylation of the PPARGC1A promoter

  • The PPARGC1A gene is an important regulator of cellular metabolism and plays a key role in the regulation of insulin secretion from the pancreas, among other functions.
  • A rare inherited mutation in this gene has been associated with reduced insulin production and an increased risk of developing Type 2 diabetes.
  • Several studies have now also shown that increased methylation (hypermethylation) of the PPARGC1A promoter in the pancreatic islet cells of Type 2 patients reduces the expression of PPARGC1A. This may result in reduced insulin production compared to healthy patients.
  • This same increased methylation of PPARGC1A has also been observed in healthy patients who are physically inactive.
  • These observations mirror the effects of the rare inherited mutation and suggest a key role for epigenetics in the development of Type 2 diabetes.

Glioblastoma patient outcomes are improved by epigenetic silencing of the MGMT promoter, an important prognostic biomarker

  • The MGMT gene encodes a DNA repair enzyme that removes harmful lesions from the genome. Hypermethylation of the MGMT promoter silences the gene (i.e. eliminates its expression), which increases the rate of mutations across the genome due to the DNA lesions which are no longer repaired. This genomic instability drives cancer progression by mutating important genes (e.g. p53) that normally suppress cell growth.
  • Ironically, reduced MGMT expression is also clinically favorable in glioblastoma because it renders the brain cancer more susceptible to a class of chemotherapeutics called alkylating agents (e.g. Temozolomide).
  • For this reason, molecular diagnostic assays that measure the methylation status of the MGMT promoter are rapidly becoming standard clinical practice in the treatment of glioblastoma and other cancers.

Alzheimer’s Disease onset is linked to epigenetic regulation of the structural protein ankyrin 1 (ANK1)

  • ANK1 is an important cytoskeletal protein that provides structure to the cell. Two leading research groups have independently demonstrated that hypermethylation significantly reduces expression of the ANK1 gene in the cortex of Alzheimer's disease patients.
  • Validation of this observation in multiple patient cohorts strongly suggests a role for epigenetics in disease onset but more work must be done. 

Finally, given the observed links between 5mC (and other DNA modifications) with disease, and also because they are quantifiable, dynamic and resistant to chemical damage from clinical sample processing (e.g. FFPE) or the environment, an inceasing amount of work is being done to realize their potential as clinical biomarkers for diagnostics, and ongoing monitoring of disease.


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Learn more about 5-hydroxymethylcytosine here.