Schizophrenia, epigenetics and ligand-activated nuclear receptors: a framework for chromatin therapeutics.
Covalent modifications of DNA and its surrounding chromatin constitute an essential and powerful regulatory mechanism for gene transcription. Epigenetics is the study of this regulatory system. There is now strong albeit indirect evidence that epigenetic mechanisms contribute to the pathophysiology of schizophrenia. Furthermore, the discovery that valproic acid, a widely used psychotropic, has powerful epigenetic effects in clinically relevant concentrations suggests new therapeutic possibilities, i.e., drugs that act on chromatin structure. Fortunately, many proteins engaged in these processes, particularly chromatin remodeling, are accessible to pharmacological agents that have a high likelihood of crossing the blood brain barrier. This review will first summarize the essentials of the epigenetic regulatory system, then address the molecular evidence for altered epigenetic mechanisms in schizophrenia, and finally focus on the retinoic acid family of ligand-activated nuclear transcription factors as a likely system for new drug development in the management of schizophrenia-related symptoms.
Sharma
Rajiv P
RP
Department of Psychiatry, University of Illinois at Chicago, 1601 West Taylor Street, Chicago, IL 60612, USA. rsharma@psych.uic.edu
D015816:Cell Adhesion Molecules, Neuronal; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D016326:Extracellular Matrix Proteins; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008715:Methionine / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism; D012697:Serine Endopeptidases; D014158:Transcription, Genetic
D015816:Cell Adhesion Molecules, Neuronal; D002843:Chromatin; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D006657:Histones; D007527:Isoenzymes; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D018168:Receptors, Retinoic Acid; D000091042:Reelin Protein; D008715:Methionine; D012697:Serine Endopeptidases; D006655:Histone Deacetylases; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1