KMT2A and KMT2B Mediate Memory Function by Affecting Distinct Genomic Regions

• DOI: 10.1016/j.celrep.2017.06.072
• Publication Date: 2017-07-18T22:47:22Z
• Authors: Cemil Kerimoglu; M. Sadman Sakib; Gaurav Jain; Eva Benito; Susanne Burkhardt; Vincenzo Capece; Lalit Kaurani; Rashi Halder; Roberto Carlos Ag...; Roman Stilling; Hendrik Urbanke; Andrea Kranz; A. Francis Stewart; Andre Fischer
• Keywords: inmunotransferencia Western; 0301 basic medicine; memoria; Genotype; hippocampus; QH301-705.5; hipocampo; alzheimer; Blotting, Western; enfermedad de Alzheimer; : Biochemistry, biophysics & molecular biology [F05] [Life sciences]; biosynthesis [Myeloid-Lymphoid Leukemia Protein]; Hippocampus; Methylation; Gene Expression Regulation, Enzymologic; memory; Mice; 03 medical and health sciences; enzymology [Hippocampus]; Alzheimer Disease; Memory; Animals; metiltransferasas; ddc:610; histone methylation; Biology (General); : Biochimie, biophysique & biologie moléculaire [F05] [Sciences du vivant]; Neurons; biosynthesis [Histone-Lysine N-Methyltransferase]; enzymology [Neurons]; inmunotransferencia western; Methyltransferases; Histone-Lysine N-Methyltransferase; genetics [Myeloid-Lymphoid Leukemia Protein]; ChIP-seq; Kmt2a protein, mouse; gene expression; Mll2; Kmt2a; genetics [Histone-Lysine N-Methyltransferase]; Mll1; Kmt2b; RNA-seq; genotipo; Alzheimer’s disease; Myeloid-Lymphoid Leukemia Protein

Kmt2a and Kmt2b are H3K4 methyltransferases of the Set1/Trithorax class. We have recently shown the importance of Kmt2b for learning and memory. Here, we report that Kmt2a is also important in memory formation. We compare the decrease in H3K4 methylation and de-regulation of gene expression in hippocampal neurons of mice with knockdown of either Kmt2a or Kmt2b. Kmt2a and Kmt2b control largely distinct genomic regions and different molecular pathways linked to neuronal plasticity. Finally, we show that the decrease in H3K4 methylation resulting from Kmt2a knockdown partially recapitulates the pattern previously reported in CK-p25 mice, a model for neurodegeneration and memory impairment. Our findings point to the distinct functions of even closely related histone-modifying enzymes and provide essential insight for the development of more efficient and specific epigenetic therapies against brain diseases.