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Histone H2A.Z subunit exchange controls consolidation of recent and remote memory

Nature volume 515, pages 582–586 (2014)Cite this article

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Abstract

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 consolidation1. Epigenetic mechanisms regulate both types of consolidation2,3,4,5,6,7, 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 brain8,9,10,11,12 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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Figure 1: H2A.Z exchange in CA1.
Figure 2: H2A.Z depletion in CA1.
Figure 3: RNA sequencing data depicting genome-wide transcriptional impact of AAV-mediated H2A.Z depletion.
Figure 4: H2A.Z depletion in mPFC.

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Acknowledgements

The authors’ work is supported by DARPA grant HR0011-12-1-0015 and NIH grants MH091122, MH57014 (J.D.S.) and NSERC-PDF grant PDF 387473-10 (I.B.Z.). We would like to thank F. Sultan for providing RNA primers and K. Alison Margolies for providing the immunohistochemistry images.

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Authors and Affiliations

  1. Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA

    Iva B. Zovkic, Brynna S. Paulukaitis, Jeremy J. Day, Deepa M. Etikala & J. David Sweatt

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  1. Iva B. Zovkic
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  2. Brynna S. Paulukaitis
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  3. Jeremy J. Day
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  4. Deepa M. Etikala
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  5. J. David Sweatt
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Contributions

J.D.S. and I.B.Z. conceived the experiments. I.B.Z. conducted the experiments and B.S.P. and D.M.E. assisted in performing the experiments. J.J.D. analysed the next-generation sequencing data.

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Correspondence to J. David Sweatt.

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The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Hippocampal H2A.Z is expressed throughout the hippocampus and is inhibited 30 min after fear conditioning.

a, b, Chromogenic staining of H2A.Z (a) and negative control (b). c, Fluorescent staining of H2A.Z (red) and DAPI (blue) shows H2A.Z distribution in CA1 and dentate gyrus (DG). d, e, H2afz mRNA expression (d; n mice per group: N = 4; C = 7; S = 2; CS = 5) and H2A.Z protein expression (e; n mice per group: N = 3; C = 3; S = 4; CS = 3) 30 min after training. f, DNA methylation at the H2afz promoter 30 min after fear conditioning (n mice per group: N = 7; C = 9; S = 5; CS = 4). N, naive; C, context; S, shock; CS, context plus shock. Data expressed as mean ± s.e.m. *Follow-up comparisons with P < 0.05.

Extended Data Figure 2 H2A.Z exchange in CA1.

H2A.Z binding at −1 nucleosome (first column for each time point) and +1 nucleosome (second column for each time point) of Egr1, Fos, Bdnf IV and Ppp1cc 30 min (left; n mice per group for Egr1 and Bdnf IV: N = 7; C = 5; S = 4; CS = 6; Ppp3ca: N = 4, C = 3, S = 3, CS = 3; n mice per group for Fos and Ppp1cc: N = 4, C = 3, S = 3, CS = 3) or 2 h (right; n mice per group: N = 10; C = 2; CS = 4; S = 6) after training. Gene expression is shown in the third column for each time point (n mice per group: N = 5, C = 6; S = 2; CS = 6; for Fos and Ppp1cc: N = 3; C = 3; S = 2; CS = 2). Data are expressed as mean ± s.e.m. *Follow-up comparisons with P < 0.05.

Extended Data Figure 3 Acetylated H2A.Z binding at the −1 and +1 nucleosomes 30 min after fear conditioning in CA1.

H2A.Zac binding was investigated at the −1 nucleosome (displayed in the first column for each set of genes) and the +1 nucleosome (displayed in the second column for each set of genes) of Npas4, Egr2, Arc and Ppp3ca (left) and Egr1, Fos, Bdnf IV and Ppp1cc genes (right) 30 min after fear conditioning. n mice per group: N = 3, C = 2; S = 4; CS = 3. N, naive; C, context; S, shock; CS, context plus shock. Data are expressed as mean ± s.e.m. *Follow-up comparisons with P < 0.05.

Extended Data Figure 4 H2A.Z expression in the mPFC after training.

a, b, H2afz expression was investigated in the mPFC 30 min (a; n mice per group: N = 2; C = 3; S = 3; CS = 3) or 2 h (b; n mice per group: N = 8; C = 5; S = 4; CS = 8) after fear conditioning. N, naive; C, context; S, shock; CS, context plus shock. Data are expressed as mean ± s.e.m.

Extended Data Figure 5 H2A.Z exchange in the mPFC.

H2A.Z binding was investigated at the −1 nucleosome (displayed in the first column for each time point) and the +1 nucleosome (displayed in the second column for each time point) of Egr1, Egr2, Arc and Ppp3ca genes 2 h (left; n mice per group: N = 4; C = 4; S = 3; CS = 5), 7 days (middle; n = 4 mice per group; n for −1 Arc and +1 Ppp3ca: N = 7; C = 6; S = 4; CS = 8) or 30 days (right; n mice per group: N = 2; C = 3; S = 3; CS = 3) after fear conditioning. N, naive; C, context; S, shock; CS, context plus shock. Data are expressed as mean ± s.e.m. *Follow-up comparisons with P < 0.05.

Extended Data Figure 6 H2A.Z exchange in the mPFC.

H2A.Z binding was investigated at the −1 nucleosome (displayed in the first column for each time point) and the +1 nucleosome (displayed in the second column for each time point) of Npas4, Fos, Bdnf IV and Ppp1cc genes 2 h (left; n mice per group: N = 4; C = 2; S = 4; CS = 6), 7 days (middle; n = 4 mice per group) or 30 days (right; n mice per group: N = 2; C = 3; S = 3; CS = 3) after fear conditioning. N, naive; C, context; S, shock; CS, context plus shock. Data are expressed as mean ± s.e.m. *Follow-up comparisons with P < 0.05.

Extended Data Figure 7 Acetylated H2A.Z binding at the −1 and +1 nucleosomes 2 h after fear conditioning in the mPFC.

H2A.Zac binding was investigated at the −1 nucleosome (displayed in the first column for each set of genes) and the +1 nucleosome (displayed in the second column for each set of genes) of Egr1, Egr2, Arc and Ppp3ca (left) and Npas4, Fos, Bdnf IV and Ppp1cc genes (right) 2 h after fear conditioning; n mice per group: N = 2; C = 4; S = 3; CS = 5. N, naive; C, context; S, shock; CS, context plus shock. Data are expressed as mean ± s.e.m. *Follow-up comparisons with P < 0.05.

Extended Data Figure 8 Acetylated H2A.Z binding at the −1 and +1 nucleosomes 7 days after fear conditioning in the mPFC.

H2A.Zac binding was investigated at the −1 nucleosome (displayed in the first column for each set of genes) and the +1 nucleosome (displayed in the second column for each set of genes) of Egr1, Egr2, Arc and Ppp3ca (left) and Npas4, Fos, Bdnf IV and Ppp1cc genes (right) 7 days after fear conditioning; n mice per group: N = 4; C = 3; S = 4; CS = 4. N, naive; C, context; S, shock; CS, context plus shock. Data are expressed as mean ± s.e.m. *Follow-up comparisons with P < 0.05.

Extended Data Figure 9 Open field test in mice receiving intra-cortical scramble or H2A.Z AAV.

a, Summary of experimental design. b, There were no differences in locomotor activity between H2A.Z mice and scramble controls. c, No group differences were found in movement velocity. d, No differences were found in vertical activity. e, There were no differences in the time spent in the centre, a widely used index of anxiety (n = 8 mice per group). Data are expressed as mean ± s.e.m.

Extended Data Table 1 The list of qPCR primers for genomic and complementary DNA
Full size table

Supplementary information

Supplementary Table 1

A list of differentially expressed genes in untrained mice 2 weeks after receiving intra-CA1 injections of scramble AAV or H2A.Z AAV. The results of directional, PolyA+ RNA sequencing identified 451 differentially expressed genes, of which 272 were increased and 179 were decreased in response to H2A.Z depletion. (XLSX 56 kb)

Supplementary Table 2

A list of differentially expressed genes in mice receiving intra-CA1 H2A.Z AAV injections with and without training. The results of directional, PolyA+ RNA sequencing identified 202 differentially expressed genes, of which 66 were increased and 136 were decreased 30 min after fear conditioning. (XLSX 32 kb)

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Zovkic, I., Paulukaitis, B., Day, J. et al. Histone H2A.Z subunit exchange controls consolidation of recent and remote memory. Nature 515, 582–586 (2014). https://doi.org/10.1038/nature13707

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