Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner

Histone modifications reflect gene activity, but the relationship between cause and consequence of transcriptional control is heavily debated. Recent developments in rewriting local histone codes of endogenous genes elucidated instructiveness of certain marks in regulating gene expression. Maintenance of such repressive epigenome editing is controversial, while stable reactivation is still largely unexplored. Here we demonstrate sustained gene re-expression using two types of engineered DNA-binding domains fused to a H3K4 methyltransferase. Local induction of H3K4me3 is sufficient to allow re-expression of silenced target genes in various cell types. Maintenance of the re-expression is achieved, but strongly depends on the chromatin microenvironment (that is, DNA methylation status). We further identify H3K79me to be essential in allowing stable gene re-expression, confirming its role in epigenetic crosstalk for stable reactivation. Our approach uncovers potent epigenetic modifications to be directly written onto genomic loci to stably activate any given gene. Epigenome editing by zinc finger (ZF) and CRISPR-dCas9 technologies can induce or repress gene expression. Here, the authors show that histone methyltransferase PRDM9 fused to either dCas9 or ZF proteins can sustain gene re-expression, and H3K79me is required for stable gene re-expression.