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Articles, Neurobiology of Disease

Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory

Mira Jakovcevski, Hongyu Ruan, Erica Y. Shen, Aslihan Dincer, Behnam Javidfar, Qi Ma, Cyril J. Peter, Iris Cheung, Amanda C. Mitchell, Yan Jiang, Cong L. Lin, Venu Pothula, A. Francis Stewart, Patricia Ernst, Wei-Dong Yao and Schahram Akbarian
Journal of Neuroscience 1 April 2015, 35 (13) 5097-5108; https://doi.org/10.1523/JNEUROSCI.3004-14.2015
Mira Jakovcevski
1Department of Psychiatry and Friedman Brain Institute and
6Max Planck Institute of Psychiatry, 80804 Munich, Germany, and
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Hongyu Ruan
3New England Primate Center, Harvard Medical School, Southborough, Massachusetts 01702,
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Erica Y. Shen
1Department of Psychiatry and Friedman Brain Institute and
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Aslihan Dincer
1Department of Psychiatry and Friedman Brain Institute and
2Department of Genetics and Genomics Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029,
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  • ORCID record for Aslihan Dincer
Behnam Javidfar
1Department of Psychiatry and Friedman Brain Institute and
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Qi Ma
2Department of Genetics and Genomics Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029,
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Cyril J. Peter
1Department of Psychiatry and Friedman Brain Institute and
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Iris Cheung
4Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01604,
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Amanda C. Mitchell
3New England Primate Center, Harvard Medical School, Southborough, Massachusetts 01702,
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Yan Jiang
1Department of Psychiatry and Friedman Brain Institute and
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Cong L. Lin
1Department of Psychiatry and Friedman Brain Institute and
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Venu Pothula
1Department of Psychiatry and Friedman Brain Institute and
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A. Francis Stewart
7Genomics BioinnovationsZentrum, Technische Universitaet, 01307 Dresden, Germany
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Patricia Ernst
5Department of Genetics and Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover New Hampshire 03755,
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Wei-Dong Yao
3New England Primate Center, Harvard Medical School, Southborough, Massachusetts 01702,
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Schahram Akbarian
1Department of Psychiatry and Friedman Brain Institute and
4Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01604,
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Abstract

Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis-regulatory sequences, but molecular and cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation of the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 (Mll1), in mouse postnatal forebrain and adult prefrontal cortex (PFC) is associated with increased anxiety and robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral phenotypes were observed after ablation of the Mll1 ortholog Kmt2b/Mll2 in PFC. Impaired working memory after Kmt2a/Mll1 ablation in PFC neurons was associated with loss of training-induced transient waves of Arc immediate early gene expression critical for synaptic plasticity. Medial prefrontal layer V pyramidal neurons, a major output relay of the cortex, demonstrated severely impaired synaptic facilitation and temporal summation, two forms of short-term plasticity essential for working memory. Chromatin immunoprecipitation followed by deep sequencing in Mll1-deficient cortical neurons revealed downregulated expression and loss of the transcriptional mark, trimethyl-H3K4, at <50 loci, including the homeodomain transcription factor Meis2. Small RNA-mediated Meis2 knockdown in PFC was associated with working memory defects similar to those elicited by Mll1 deletion. Therefore, mature prefrontal neurons critically depend on maintenance of Mll1-regulated H3K4 methylation at a subset of genes with an essential role in cognition and emotion.

  • ChIP-seq
  • histone H3-lysine 4 methylation
  • neuroepigenetics
  • neuronal nuclei sorting
  • short-term plasticity
  • working memory
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The Journal of Neuroscience: 35 (13)
Journal of Neuroscience
Vol. 35, Issue 13
1 Apr 2015
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Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory
Mira Jakovcevski, Hongyu Ruan, Erica Y. Shen, Aslihan Dincer, Behnam Javidfar, Qi Ma, Cyril J. Peter, Iris Cheung, Amanda C. Mitchell, Yan Jiang, Cong L. Lin, Venu Pothula, A. Francis Stewart, Patricia Ernst, Wei-Dong Yao, Schahram Akbarian
Journal of Neuroscience 1 April 2015, 35 (13) 5097-5108; DOI: 10.1523/JNEUROSCI.3004-14.2015

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Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory
Mira Jakovcevski, Hongyu Ruan, Erica Y. Shen, Aslihan Dincer, Behnam Javidfar, Qi Ma, Cyril J. Peter, Iris Cheung, Amanda C. Mitchell, Yan Jiang, Cong L. Lin, Venu Pothula, A. Francis Stewart, Patricia Ernst, Wei-Dong Yao, Schahram Akbarian
Journal of Neuroscience 1 April 2015, 35 (13) 5097-5108; DOI: 10.1523/JNEUROSCI.3004-14.2015
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Keywords

  • ChIP-seq
  • histone H3-lysine 4 methylation
  • neuroepigenetics
  • neuronal nuclei sorting
  • short-term plasticity
  • working memory

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  • THOUGHTS AS KNOTS
    Arturo Tozzi
    Published on: 24 April 2015
  • Published on: (24 April 2015)
    Page navigation anchor for THOUGHTS AS KNOTS
    THOUGHTS AS KNOTS
    • Arturo Tozzi, MD, PhD
    • Other Contributors:
      • Carlo Venditti

    Jakovcevski et al. suggest a possible molecular role for prefrontal methyltransferases in working memory, emotion and cognition. Such an interesting observation throws an unexpected bridge between topology, molecular assemblies and brain function. Methyltransferases are among the rare enzymes exhibiting the weird property of... a knot in their backbone. In other words, they are proteins with structures that do not disent...

    Show More

    Jakovcevski et al. suggest a possible molecular role for prefrontal methyltransferases in working memory, emotion and cognition. Such an interesting observation throws an unexpected bridge between topology, molecular assemblies and brain function. Methyltransferases are among the rare enzymes exhibiting the weird property of... a knot in their backbone. In other words, they are proteins with structures that do not disentangle completely after being pulled from both ends (Virnau et al., 2011). A knot is indeed the embedding of a closed line in the 3D space and cannot be reduced to a simple circle by a continuous deformation (Wu, 1992). The knot theory arises from topology and provides tools for cataloguing different types of knots, for possibly transforming one into another via a deformation of 3D space upon itself and for summing different knots in assemblages equipped with commutative and associative properties (Cromwell, 2004). In turn, the recently developed concept of "supramolecular chemistry" suggests that complex chemical entities can be reversibly constructed from molecular components bound together by labile non-covalent interactions (Lehn, 2007). The novel idea involves the storage of information at the molecular level and its retrieval, transfer and processing at the supramolecular level, via transitory processes that are self-organized, self-assembled and dynamic (Taylor and Ehrenreich, 2014). Incorporating such different perspectives appears to be particularly relevant for understanding how the brain does represent the stimuli coming from the environment and the internally directed, spontaneous deliberate self-generated thought (Andrews-Hanna et al., 2014). Recent findings suggest that nervous structures could process information through topological, other than spatial, mechanisms: for example, it is believed that hippocampal place cells create a topological template to represent spatial information (Dabanghian et al., 2014). Further, structures quite different from spikes, such as macromolecular assemblies, may play a role in information processing in nervous system: we do not yet understand to what extent the diffusion and biophysical cues, such as the mechanical properties of the extracellular matrix (Sur et al., 2013), have to be taken into account when talking about the brain function. In conclusion, the thoughts could be metaphorically compared with open strings made of proteins and/or supramolecular assemblies, a sort of random-walks wandering around in the viscous fluid of the nervous melieu. The entanglement of their extremities may give rise to reversible or irreversible topological knots, respectively standing for labile or enduring perceptions and memories.

    1) Andrews-Hanna JR., Smallwood J, Spreng RN (2014) The default network and self-generated thought: component processes, dynamic control, and clinical relevance. Ann NY Acad Sci 1316:29-52. doi: 10.1111/nyas.12360.

    2) Cromwell PR. Knots and Links (2004) Cambridge University Press, Cambridge. ISBN: 9780521548311.

    3) Dabaghian Y, Brandt VL, Frank LM (2014). Reconceiving the hippocampal map as a topological template. eLife 10.7554/eLife.03476. doi: http://dx.doi.org/10.7554/eLife.03476

    4) Lehn JM (2007) From supramolecular chemistry towards constitutional dynamic chemistry and adaptive chemistry. Chem Soc Rev 36(2):151-160.

    5) Sur S, Newcomb CJ, Webber MJ, Stupp SI (2013) Tuning supramolecular mechanics to guide neuron development. Biomaterials 34(20):4749-4757. doi: 10.1016/j.biomaterials.2013.03.025

    6) Taylor MB, Ehrenreich IM (2014) Genetic interactions involving five or more genes contribute to a complex trait in yeast. PLoS Genet 10(5):e1004324. doi: 10.1371/journal.pgen.1004324.

    7) Virnau P, Mallam A, Jackson S (2011) Structures and folding pathways of topologically knotted proteins. J. Phys.: Condens. Matter 23 033101. doi:10.1088/0953-8984/23/3/033101

    8) Wu FY. Knot theory and statistical mechanics (1992) Rev Mod Phys, 64 (4) 1099-1131.

    Conflict of Interest:

    None declared

    Show Less
    Competing Interests: None declared.

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