DNA methylation and transcriptional noise

Background: DNA methylation is one of the most phylogenetically widespread epigenetic modifications of genomic DNA. In particular, DNA methylation of transcription units ('gene bodies') is highly conserved across diverse taxa. However, the functional role of gene body methylation is not yet fully understood. A long-standing hypothesis posits that gene body methylation reduces transcriptional noise associated with spurious transcription of genes. Despite the plausibility of this hypothesis, an explicit test of this hypothesis has not been performed until now. Results: Using nucleotide-resolution data on genomic DNA methylation and abundant microarray data, here we investigate the relationship between DNA methylation and transcriptional noise. Transcriptional noise measured from microarrays scales down with expression abundance, confirming findings from single-cell studies. We show that gene body methylation is significantly negatively associated with transcriptional noise when examined in the context of other biological factors. Conclusions: This finding supports the hypothesis that gene body methylation suppresses transcriptional noise. Heavy methylation of vertebrate genomes may have evolved as a global regulatory mechanism to control for transcriptional noise. In contrast, promoter methylation exhibits positive correlations with the level of transcriptional noise. We hypothesize that methylated promoters tend to undergo more frequent transcriptional bursts than those that avoid DNA methylation.