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J Neurosci. 2015 Apr 1;35(13):5097-108. doi: 10.1523/JNEUROSCI.3004-14.2015.

Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory.

Author information

1
Department of Psychiatry and Friedman Brain Institute and Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
2
New England Primate Center, Harvard Medical School, Southborough, Massachusetts 01702.
3
Department of Psychiatry and Friedman Brain Institute and.
4
Department of Psychiatry and Friedman Brain Institute and Department of Genetics and Genomics Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
5
Department of Genetics and Genomics Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
6
Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01604.
7
Genomics BioinnovationsZentrum, Technische Universitaet, 01307 Dresden, Germany.
8
Department of Genetics and Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover New Hampshire 03755.
9
New England Primate Center, Harvard Medical School, Southborough, Massachusetts 01702, Schahram.akbarian@mssm.edu yaow@upstate.edu.
10
Department of Psychiatry and Friedman Brain Institute and Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01604, Schahram.akbarian@mssm.edu yaow@upstate.edu.

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.

KEYWORDS:

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

PMID:
25834037
PMCID:
PMC4380991
DOI:
10.1523/JNEUROSCI.3004-14.2015
[Indexed for MEDLINE]
Free PMC Article

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