Promoter DNA Hypermethylation and Paradoxical Gene Activation

The paradigm of promoter DNA methylation as a transcriptional silencing mechanism does not always hold true. In a growing number of studies in different biological contexts, promoter hypermethylation is associated with gene activation. Hypermethylation-induced transcriptional activation has been documented in a range of cellular changes, including development, malignancy, and metastatic disease. This phenomenon may represent a new mechanism of gene regulation in human development, tumourigenesis, and metastasis. The molecular basis of hypermethylation-induced gene activation is currently unclear. Further exploration of hypermethylation-induced transcriptional activation may identify novel biomarkers and therapeutic targets, particularly with respect to malignancy and tumour progression. DNA methylation is a stable epigenetic modification that contributes to the spatiotemporal regulation of gene expression. The manner in which DNA methylation contributes to transcriptional control is dependent on the biological context, including physiological state and the properties of the DNA itself. Classically, dense promoter DNA methylation is associated with transcriptional repression. However, growing evidence suggests that this association may not always hold true, and promoter hypermethylation now also appears to be associated with high transcriptional activity. Furthermore, in a selection of contexts, increasing levels of promoter methylation correlate directly with increased gene expression. These findings postulate a context-dependent model whereby epigenetic contributions to transcriptional regulation occur in a more complex and dynamic manner. We present current evidence documenting promoter hypermethylation and high levels of gene expression, offer insights into the possible mechanisms by which this occurs, and discuss the potential implications for both research and clinical applications. DNA methylation is a stable epigenetic modification that contributes to the spatiotemporal regulation of gene expression. The manner in which DNA methylation contributes to transcriptional control is dependent on the biological context, including physiological state and the properties of the DNA itself. Classically, dense promoter DNA methylation is associated with transcriptional repression. However, growing evidence suggests that this association may not always hold true, and promoter hypermethylation now also appears to be associated with high transcriptional activity. Furthermore, in a selection of contexts, increasing levels of promoter methylation correlate directly with increased gene expression. These findings postulate a context-dependent model whereby epigenetic contributions to transcriptional regulation occur in a more complex and dynamic manner. We present current evidence documenting promoter hypermethylation and high levels of gene expression, offer insights into the possible mechanisms by which this occurs, and discuss the potential implications for both research and clinical applications.