DNMT3L and Dravet syndrome: Together, these findings (summarized in Fig. 1) demonstrate that early neuronal DNMT3L overexpression recreates a facet of the genome-wide DS DNA methylation signature, specifically the gene loci that consistently display hyper-methylation in DS such as RUNX1. These results also suggest that DNMT3L may be a major contributor to the hypermethylated bivalent chromatin signature in DS, while RUNX1 binding and demethylation may be a contributor to the blood-specific hypomethylated signature of DS.