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

55 Scopus citations


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
Issue number12
StatePublished - Dec 2020
Externally publishedYes

Bibliographical note

Funding Information:
We thank E. Niederst, J. Penney, S. Barker, R.T. Stott, M. Victor, A. Watson, N. Dedic, E. Lockshin and the members of the L.-H.T. Lab for helpful discussion and suggestions. We thank lab manager Y. Zhou and E. McNamara for mice colony maintenance. We thank P. Autissier (Whitehead Institute) for help with FACS. This work was supported by National Institutes of Health (NIH) grants RF1AG062377, AF1AG054012, RO1NS102730 and RF1AG064321, the JPB Foundation, the Alana Foundation, the LuMind Down Syndrome Foundation, the Cure Alzheimer’s Fund CIRCUITS consortium and the Robert A. and Renee E. Belfer Family Foundation to L.-H.T. This work was also supported, in part, by NIH grants R01AG058002, U01NS110453, R01AG062335 and UG3NS115064 to M.K. and L.-H.T. and R01AG067151, R01MH109978, U01MH119509, R01HG008155 and U24HG009446 to M.K. V.D. is supported by the AARF-19-618751 grant from the Alzheimer’s Association. H.S.M. is supported by the Burroughs Wellcome Fund and a UNCF–Merck postdoctoral fellowship. C.A. is supported by the JPB Foundation. R.M.R. is supported by NIH T32 grant 5T32HD09806. The Hi-C libraries preparation kit was received as a generous gift from DovetailTM (v.1.03, Dovetail Genomics). We thank the Dovetail team for helpful discussion and suggestions.

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


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