Cell-type- and locus-specific epigenetic editing of memory expression.

Epigenetic mechanisms have long been proposed to act as molecular mnemonics1-3, but whether the epigenetic makeup of a single genomic site can guide learnt behaviors remains unknown. Here we combined CRISPR-based epigenetic editing tools4,5 with c-Fos-driven engram technologies6,7 to address this question in memory-bearing neuronal ensembles. Focusing on the promoter of Arc, which encodes a master regulator of synaptic plasticity8, we found that its locus-specific and temporally controlled epigenetic editing is necessary and sufficient to regulate memory expression. Such effects occurred irrespective of the memory phase-during the initially labile period after learning and for fully consolidated memories-and were reversible within subject, testifying to their inherent plasticity. These findings provide a proof-of-principle that site-specific epigenetic dynamics are causally implicated in memory expression.