Galonska, C. et al. Nat. Commun. 9, 597 (2018).

Everybody agrees that DNA methylation has important regulatory roles, but many blanks regarding the details of this regulation remain to be filled in. The advent of CRISPR brought the promise of targeted modification of cytosines by fusing a methyltransferase to dCas9 and directing it to a locus of interest via guide RNAs (gRNAs). Galonska et al. examined this promise in a mouse embryonic stem cell line devoid of any DNA methylation and observed unexpectedly high background methylation, independent of gRNAs. The researchers replicated this finding in two somatic human cell lines; although they saw on-target activity at loci with low endogenous methylation, they also observed high genome-wide off-target activity. dCas9 fused to epigenetic effector proteins is a valuable tool, but more work is needed to ensure specificity.