On the enigmatic null effect of global methylation perturbation

Despite the established role of DNA methylation in transcriptional silencing, most of the genes remain unchanged upon its global erasing from the genome, while expression of other genes is actually raised. Since its discovery a few decades ago, this unsolved enigma has hampered true understanding of DNA methylation role. By applying an updated mathematical model to the results of the original studies, we showed that this paradoxical effect is due to between-gene differences in the balance between methylation-guided enhancers and silencers, which protect particular disease-causing genes from the otherwise harsh effects of global methylation perturbation. Nevertheless, local methylation alternation may still affect these genes. The results a settle a long-standing wondering and suggest that DNA-methylation regulatory role is significantly greater than previously thought.