DNA Methylation and Gene Regulation

DNA methylation is thought to be a powerful epigenetic mechanism which interferes with the binding of transcription factor proteins and establishes a silent chromatin state.

Recent studies suggest that three DNA methyltransferase enzymes (DNMT1, DNMT3a and DNMT3b) are responsible for the addition of methyl groups to cytosine (de novo methylation) as well as maintaining a dinucleotide’s methylation status during DNA replication. Although not completely understood, DNMT3a and DNMT3b enzymes are catalysts in the origin of DNA methylation (Okano 1999).  While not involved in de novo methylation, the DNMT1 enzyme plays a role where methylation patterns are stably maintained across cell generations.

A small but significant proportion of all CpG islands become methylated during development, and when this happens, the associated promoter is stably silent. Although not fully understood, evidence suggests this occurs when the methyl group interferes with the binding of transcription factor proteins or by chromatin remodeling via methylation-dependant, CpG-binding domain proteins (MBD) (Bird and Wolffe 1999).

Several lines of evidence suggest that the methyl group in some cases directly interferes with the binding of transcription factors that activate transcription. In an alternative process, CpG-binding domain (MBD) proteins bind to the methyl group and subsequently to chromatin remodeling proteins (such as histone deacetylases) to silence the gene by making it transcriptionally unavailable. Genes that are methylated tend to be packaged more tightly, which causes them to be silenced. Genes that are not methylated tend to exhibit looser packaging, which allows their expression.