Histone H2A.Z subunit exchange controls consolidation of recent and remote memory
Open accessAbstract
Memory formation is a multi-stage process that initially requires cellular consolidation in the hippocampus, after which memories are downloaded to the cortex for maintenance, in a process termed systems consolidation. Epigenetic mechanisms regulate both types of consolidation, but histone variant exchange, in which canonical histones are replaced with their variant counterparts, is an entire branch of epigenetics that has received limited attention in the brain and has never, to our knowledge, been studied in relation to cognitive function. Here we show that histone H2A.Z, a variant of histone H2A, is actively exchanged in response to fear conditioning in the hippocampus and the cortex, where it mediates gene expression and restrains the formation of recent and remote memory. Our data provide evidence for H2A.Z involvement in cognitive function and specifically implicate H2A.Z as a negative regulator of hippocampal consolidation and systems consolidation, probably through downstream effects on gene expression. Moreover, alterations in H2A.Z binding at later stages of systems consolidation suggest that this histone has the capacity to mediate stable molecular modifications required for memory retention. Overall, our data introduce histone variant exchange as a novel mechanism contributing to the molecular basis of cognitive function and implicate H2A.Z as a potential therapeutic target for memory disorders.
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Previous studies have shown the importance of histones in DNA damage response, senescence, brain aging, neuronal identity, and memory formation.
“Previous studies have shown the importance of histones in DNA damage response, senescence, brain aging, neuronal identity, and memory formation100–102,136–139.”
From Neuronal DNA double-strand breaks lead to genome structural variations and 3D genome disruption in neurodegeneration (2023) · cites this paper as [102]
Thirty minutes after memory acquisition, histone variant H2A.Z binding around the transcription start site becomes altered, which consequently affects the expression of immediate-early genes.
“For instance, 30 min after memory acquisition, histone variant H2A.Z binding around the transcription start site becomes altered, which consequently affects the expression of immediate-early genes (IEGs).”
From Role of the hippocampus in systems consolidation of remote fear memory (2026) · cites this paper as [48]
Depletion of H2A.Z in the CA1 region enhanced both 1-day and 2-week fear memory, which was accompanied by changes in immediate-early gene expression patterns.
“Depletion of H2A.Z in the CA1 region enhanced both 1-day and 2-week fear memory, which was accompanied by changes in IEG expression patterns 48 .”
From Role of the hippocampus in systems consolidation of remote fear memory (2026) · cites this paper as [48]
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- Authors
- Zovkic, I. B., Paulukaitis, B. S., Day, J. J., Etikala, D. M., & Sweatt, J. D.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Sweatt, J. David
- Venue
- Nature
- Published
- 2014-09-14
- Volume
- 515
- Issue
- 7528
- Pages
- 582-586
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4768489
- OpenAlex
- W2072002750
- Cited by
- 179
- References
- 29
- Citations by year
- 2026: 9 · 2025: 17 · 2024: 11 · 2023: 7 · 2022: 8 · 2021: 23 · 2020: 10 · 2019: 19 · 2018: 14 · 2017: 20 · 2016: 20 · 2015: 16 · 2014: 5
- FWCI
- 11.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- Defense Advanced Research Projects Agency
- National Institute of Mental Health (MH091122, MH 57014, R01MH091122, R01MH057014)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory Processes and Influences
- Keywords
- histone H2A.Z, histone variant exchange, memory consolidation, systems consolidation, hippocampus, fear conditioning, remote memory, epigenetic regulation, memory stabilization, memory disorders
- MeSH terms
- Animals, Cognition, Conditioning, Psychological, Fear, Gene Expression Regulation, Hippocampus, Histones, Male, Memory, Mice, Inbred C57BL, Protein Binding, Epigenesis, Genetic, Mice, Gene Knockdown Techniques
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