Histone variant exchange is a novel epigenetic regulator of cognition. We speculate that H2A.Z, a variant of canonical histone H2A, exerts unique effects on transcription during distinct stages of memory formation, ultimately acting to maintain memory of previous transcriptional states and poise genes for re‐activation. Hippocampus‐dependent memory formation is initiated by transient expression of memory‐related genes, which support the storage of recently acquired memories. Soon after, memories undergo systems consolidation, which transfers memories from the hippocampus to the cortex for long‐term storage, and requires ongoing re‐activation of memory‐related genes. We speculate that learning‐induced H2A.Z eviction from nucleosomes initially contributes to stimulus‐induced transcriptional induction needed for the initial process of memory consolidation. During systems consolidation, we speculate that delayed incorporation of H2A.Z into nucleosomes of memory‐related genes in the cortex is needed to poise genes for rapid re‐activation, thus supporting the long‐term process of memory stabilization.
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