title: Neuronal Kmt2a/Mll1 histone methyltransferase is essential for prefrontal synaptic plasticity and working memory.
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.
authors.affiliation: Department of Psychiatry and Friedman Brain Institute and Max Planck Institute of Psychiatry, 80804 Munich, Germany, and.
authors.forename: Mira
authors.initials: M
authors.lastname: Jakovcevski
authors.affiliation: New England Primate Center, Harvard Medical School, Southborough, Massachusetts 01702.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ruan
authors.affiliation: Department of Psychiatry and Friedman Brain Institute and.
authors.forename: Erica Y
authors.initials: EY
authors.lastname: Shen
authors.affiliation: 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.
authors.forename: Aslihan
authors.identifier: http://orcid.org/0000-0002-4971-1597
authors.initials: A
authors.lastname: Dincer
authors.affiliation: Department of Psychiatry and Friedman Brain Institute and.
authors.forename: Behnam
authors.initials: B
authors.lastname: Javidfar
authors.affiliation: Department of Genetics and Genomics Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York 10029.
authors.forename: Qi
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Psychiatry and Friedman Brain Institute and.
authors.forename: Cyril J
authors.identifier: http://orcid.org/0000-0001-9190-8724
authors.initials: CJ
authors.lastname: Peter
authors.affiliation: Brudnick Neuropsychiatric Research Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01604.
authors.forename: Iris
authors.initials: I
authors.lastname: Cheung
authors.affiliation: New England Primate Center, Harvard Medical School, Southborough, Massachusetts 01702.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Mitchell
authors.affiliation: Department of Psychiatry and Friedman Brain Institute and.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Psychiatry and Friedman Brain Institute and.
authors.forename: Cong L
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Department of Psychiatry and Friedman Brain Institute and.
authors.forename: Venu
authors.initials: V
authors.lastname: Pothula
authors.affiliation: Genomics BioinnovationsZentrum, Technische Universitaet, 01307 Dresden, Germany.
authors.forename: A Francis
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: Department of Genetics and Department of Microbiology and Immunology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Hanover New Hampshire 03755.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ernst
authors.affiliation: New England Primate Center, Harvard Medical School, Southborough, Massachusetts 01702, Schahram.akbarian@mssm.edu yaow@upstate.edu.
authors.forename: Wei-Dong
authors.initials: WD
authors.lastname: Yao
authors.affiliation: 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.
authors.forename: Schahram
authors.initials: S
authors.lastname: Akbarian
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000187:drug effects / Q000235:genetics; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008745:Methylation; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D051788:Myeloid-Lymphoid Leukemia Protein / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000502:physiology*; D017397:Prefrontal Cortex / Q000502:physiology*; D016548:Prosencephalon / Q000502:physiology; D017966:Pyramidal Cells / Q000502:physiology
chemical_list: D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; C102641:Mrg1 protein, mouse; D009419:Nerve Tissue Proteins; C092069:activity regulated cytoskeletal-associated protein; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse
keywords: ChIP-seq; histone H3-lysine 4 methylation; neuroepigenetics; neuronal nuclei sorting; short-term plasticity; working memory
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