The mirage of DNA methylation in transcriptional regulation of plants.

"Cytosine methylation plays an important role in the regulation of gene expression in plants." Some iteration of this statement can be found in most papers centered on plant epigenetics and has become a widely accepted textbook claim. However, our generalized understanding of how DNA methylation exerts control over transcription is now challenged by observations demonstrating that transcriptional levels of most genes are unresponsive to DNA methylation changes. On a genome-wide scale, associations between DNA methylation and transcription are usually statistically weak. Even when correlations are found, the cause and effect can be difficult to identify, as methylation changes sometimes follow rather than precede transcriptional changes. While a growing number of studies explore a possible connection between differentially expressed genes (DEGs) and differentially methylated genes (DMGs), we demonstrate here that DEG-DMG overlaps are often significantly smaller than what could be expected by chance. This indicates that, contrary to expectations, changes in DNA methylation and changes in transcription sometimes avoid one another. Here, we discuss such observations and their implications for the hypothesis of a widespread control of gene expression directly by DNA methylation. While there are well-documented examples where DNA methylation regulates transcription, we argue that such cases represent a minority of genes, and we opine that approaches of reverse epigenetics are therefore unlikely to find broad application in breeding.