Abstract

The ability to form memories is a prerequisite for an organism's behavioral adaptation to environmental changes. At the molecular level, the acquisition and maintenance of memory requires changes in chromatin modifications. In an effort to unravel the epigenetic network underlying both short- and long-term memory, we examined chromatin modification changes in two distinct mouse brain regions, two cell types and three time points before and after contextual learning. We found that histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression. Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning. Finally, our data provide evidence for a molecular framework of memory acquisition and maintenance, wherein DNA methylation could alter the expression and splicing of genes involved in functional plasticity and synaptic wiring.

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Acknowledgements

We would like to thank M. Boroomandi for help with the behavioral experiments. We would like to thank E.E. Furlong, A.G. Ladurner, C. Margulies, R.P. Zinzen and W. Jackson for critical reading of the manuscript. This work was supported by the DFG (BO4224/4-1) (S. Bonn), the Network of Centres of Excellence in Neurodegeneration (CoEN) initiative (S. Bonn and A.F.), iMed – the Helmholtz Initiative on Personalized Medicine (S. Bonn and A.F.), the EURYI Award of the ESF (A.F.), the Hans and Ilse Breuer Foundation (A.F.), and by the European Research Council under the European Union's Seventh Framework Program (FP7/2007–2013)/ ERC Grant Agreement No. 321366-Amyloid (advanced grant to C.H.).

Author information

Author notes

    • Rashi Halder
    • , Magali Hennion
    •  & Ramon O Vidal

    These authors contributed equally to this work.

Affiliations

  1. Research Group for Epigenetic Mechanisms in Dementia, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

    • Rashi Halder
    • , Susanne Burkhardt
    • , Eva Benito
    • , Magdalena Navarro Sala
    • , Sanaz Bahari Javan
    •  & Andre Fischer
  2. Research Group for Computational Systems Biology, German Center for Neurodegenerative Diseases (DZNE), Göttingen, Germany.

    • Magali Hennion
    • , Ramon O Vidal
    • , Orr Shomroni
    • , Raza-Ur Rahman
    • , Ashish Rajput
    • , Tonatiuh Pena Centeno
    • , Vincenzo Capece
    • , Julio C Garcia Vizcaino
    • , Anna-Lena Schuetz
    •  & Stefan Bonn
  3. German Center of Neurodegenerative Diseases (DZNE), Munich, Germany.

    • Frauke van Bebber
    • , Christian Haass
    •  & Bettina Schmid
  4. Biomedical Center, Ludwig Maximilians University Munich, Munich, Germany.

    • Christian Haass
  5. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.

    • Christian Haass
    •  & Bettina Schmid
  6. Department of Psychiatry and Psychotherapy, University Medical Center, Göttingen, Germany.

    • Andre Fischer

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Contributions

S. Bonn initiated the study and designed the experiments with A.F., R.H., M.H. and R.O.V. S. Burkhardt, M.N.S., R.H. and S.B.J. performed the behavioral experiments. F.v.B., C.H. and B.S. performed the zebrafish experiments. A.-L.S., S. Burkhardt, R.H. and M.H. were responsible for the library generation and sequencing of the samples. M.H., R.H., A.R. and E.B. conducted all other experiments and analyzed the data. R.O.V., O.S., R.-U.R., T.P.C., J.C.G.V., V.C., S. Bonn, R.H. and M.H. were responsible for the computational analysis of the data. S. Bonn, M.H. and R.O.V. wrote the manuscript. All of the authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Andre Fischer or Stefan Bonn.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–30

  2. 2.

    Supplementary Methods Checklist

Excel files

  1. 1.

    Supplementary Table 1: ChIP- and MeDIP-seq antibodies.

    Detailed information on the antibodies used for ChIP- and MeDIP-seq experiments and their usage.

  2. 2.

    Supplementary Table 2: DEGs and DEEs.

    Overview over all DEGs and DEEs for the different time-points, learning comparisons, and brain areas. Additional information on in vitro DEGs after KCl stimulation.

  3. 3.

    Supplementary Table 3: Sequencing samples and quality.

    Summarization of ChIP-, MeDIP-, and RNA-seq samples and their corresponding quality metrics.

  4. 4.

    Supplementary Table 4: Known cell type-specific genes.

    Table containing the genes that were categorized as neuron- or glia-specific based on published information.

  5. 5.

    Supplementary Table 5: Predicted cell type-specific genes.

    Table of the predicted cell-type specific genes in the CA1 and ACC, in neurons and non-neurons.

  6. 6.

    Supplementary Table 6: Predicted CRMs.

    Table of the predicted cell-type specific CRMs in the CA1 and ACC, in neurons and non-neurons.

  7. 7.

    Supplementary Table 7: Validated CRMs.

    Detailed information on the CRMs that cloned and validated in Danio rerio enhancer assays.

  8. 8.

    Supplementary Table 8: Differential HPTMs.

    Lists of genes containing DHPTMs for the in vivo and in vitro data and summary information.

  9. 9.

    Supplementary Table 9: Primer.

    Table summarizing information of the ChIP, expression, and MeDIP qPCR primers used.

  10. 10.

    Supplementary Table 10: DHPTM-DEG overview.

    Information on DHPTM-DEG comparisons for the different histone modifications, learning comparisons, and cell types.

  11. 11.

    Supplementary Table 11: DMRs and DMGs.

    Overview over all DMRs for the different time-points, learning comparisons, brain areas, and cell types.

  12. 12.

    Supplementary Table 12: DMG-DEG-DEE overview.

    Information on DMG-DEG and DMG-DEE comparisons for the different time-points, learning comparisons, brain areas, and cell types.

Zip files

  1. 1.

    Supplementary Data Set

    Interactive Enrichment Files

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DOI

https://doi.org/10.1038/nn.4194