New mechanisms in memory storage: piRNAs and epigenetics

•Epigenetics offers new insights into mechanisms of long-term memory storage.•What provides spatiotemporal specificity of epigenetic regulation during memory?•Recent studies on small RNAs can offer an answer and perspective.•We review small-RNA mediated epigenetic mechanisms underlying memory storage.

In recent years, a greater understanding has emerged of the role epigenetic mechanisms play in the brain, not only during development, but also in mature neurons involved in long-term memory. The identification of spatially and temporally tuned epigenetic modification of genetic loci during memory storage has revealed the remarkably input-responsive, target-specific, and long-term nature of epigenetic regulation, but the underlying mechanisms have remained elusive. New insight into these mechanisms has come from the study of small RNAs, which have emerged as regulators that can confer sequence specificity to DNA- and chromatin-modifying processes. We discuss advances in the elucidation of the epigenetic mechanisms involved in long-term memory, focusing on the role of small RNAs, and in particular piwi-interacting RNAs (piRNAs), in the epigenetic regulation underlying memory storage.