Mapping the epigenomic and transcriptomic interplay during memory formation and recall in the hippocampal engram ensemble

Asaf Marco*, Hiruy S. Meharena, Vishnu Dileep, Ravikiran M. Raju, Jose Davila-Velderrain, Amy Letao Zhang, Chinnakkaruppan Adaikkan, Jennie Z. Young, Fan Gao, Manolis Kellis, Li Huei Tsai*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

The epigenome and three-dimensional (3D) genomic architecture are emerging as key factors in the dynamic regulation of different transcriptional programs required for neuronal functions. In this study, we used an activity-dependent tagging system in mice to determine the epigenetic state, 3D genome architecture and transcriptional landscape of engram cells over the lifespan of memory formation and recall. Our findings reveal that memory encoding leads to an epigenetic priming event, marked by increased accessibility of enhancers without the corresponding transcriptional changes. Memory consolidation subsequently results in spatial reorganization of large chromatin segments and promoter–enhancer interactions. Finally, with reactivation, engram neurons use a subset of de novo long-range interactions, where primed enhancers are brought in contact with their respective promoters to upregulate genes involved in local protein translation in synaptic compartments. Collectively, our work elucidates the comprehensive transcriptional and epigenomic landscape across the lifespan of memory formation and recall in the hippocampal engram ensemble.

Original languageAmerican English
Pages (from-to)1606-1617
Number of pages12
JournalNature Neuroscience
Volume23
Issue number12
DOIs
StatePublished - Dec 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

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