Covalent modification of DNA regulates memory formation.
DNA methylation is a covalent chemical modification of DNA catalyzed by DNA methyltransferases (DNMTs). DNA methylation is associated with transcriptional silencing and has been studied extensively as a lifelong molecular information storage mechanism put in place during development. Here we report that DNMT gene expression is upregulated in the adult rat hippocampus following contextual fear conditioning and that DNMT inhibition blocks memory formation. In addition, fear conditioning is associated with rapid methylation and transcriptional silencing of the memory suppressor gene PP1 and demethylation and transcriptional activation of the synaptic plasticity gene reelin, indicating both methyltransferase and demethylase activity during consolidation. DNMT inhibition prevents the PP1 methylation increase, resulting in aberrant transcription of the gene during the memory-consolidation period. These results demonstrate that DNA methylation is dynamically regulated in the adult nervous system and that this cellular mechanism is a crucial step in memory formation.
Miller
Courtney A
CA
Department of Neurobiology and the Evelyn F. McKnight Brain Institute,University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Sweatt
J David
JD
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001522:Behavior, Animal; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D003214:Conditioning, Classical / Q000502:physiology; D004247:DNA / Q000502:physiology*; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D005239:Fear; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000091042:Reelin Protein; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism
D015816:Cell Adhesion Molecules, Neuronal; D004791:Enzyme Inhibitors; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; D000077209:Decitabine; D004247:DNA; D004248:DNA (Cytosine-5-)-Methyltransferases; D010749:Phosphoprotein Phosphatases; D012697:Serine Endopeptidases; D001374:Azacitidine