Epigenetic regulation of a gene is the process by which the activity of a particular gene is controlled by the structure of nearby chromatin.
Chromatin remodelling is complex and involves covalent modification of histones (for example, acetylation, methylation and phosphorylation), ATPase-containing protein complexes that move histone oligomers along a strand of DNA, direct methylation of DNA, and the binding of numerous transcription factors and transcriptional co-activators and co-repressors, all of which act in a concerted fashion to determine the activity of a given gene.
Epigenetic regulation is crucial for nervous system development, and several common mental retardation syndromes and related neurodevelopmental disorders are caused by abnormalities in chromatin remodelling mechanisms.
Epigenetic regulation also occurs in the mature brain, and may underlie stable changes in gene expression both under normal conditions (for example, learning and memory) and in several neuropathological states.
Long-lasting changes in histone acetylation, histone methylation and DNA methylation have been demonstrated in rodent models of depression. Drugs that increase histone acetylation exert antidepressant-like effects in these models.
Some of the lasting effects on the brain of drugs of abuse such as cocaine have been related to the drug's regulation of histone acetylation. Agents that increase histone acetylation enhance biochemical and behavioural responses to cocaine, and mice lacking certain enzymes that mediate histone deacetylation show similar increases in cocaine responsiveness.
Rett syndrome, an autism spectrum disorder, is caused by loss of function mutations in the gene that encodes a protein that binds to methylated sites in DNA and acts to repress the associated genes.
Recent work has implicated abnormalities in DNA methylation and histone acetylation in schizophrenia.
Work on epigenetic mechanisms of psychiatric disorders is in its early stages, but promises to improve our understanding of disease pathophysiology and might lead to the development of fundamentally new treatments for these conditions.
Many neurological and most psychiatric disorders are not due to mutations in a single gene; rather, they involve molecular disturbances entailing multiple genes and signals that control their expression. Recent research has demonstrated that complex 'epigenetic' mechanisms, which regulate gene activity without altering the DNA code, have long-lasting effects within mature neurons. This review summarizes recent evidence for the existence of sustained epigenetic mechanisms of gene regulation in neurons that have been implicated in the regulation of complex behaviour, including abnormalities in several psychiatric disorders such as depression, drug addiction and schizophrenia.
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Kendler, K. S. Twin studies of psychiatric illness: an update. Arch. Gen. Psychiatry 58, 1005–1014 (2001).
Hyman, S. E. & Nestler, E. J. The Molecular Foundations of Psychiatry (American Psychiatric, Washington, D. C., 1993).
McClung, C. A. et al. ΔFosB: a molecular switch for long-term adaptation in the brain. Brain Res. Mol. Brain Res. 132, 146–154 (2004).
Nestler, E. J., Barrot, M. & Self, D. W. ΔFosB: a sustained molecular switch for addiction. Proc. Natl Acad. Sci. USA 98, 11042–11046 (2001).
Felsenfeld, G. & Groudine, M. Controlling the double helix. Nature 421, 448–453 (2003).
Hake, S. B., Xiao, A. & Allis, C. D. Linking the epigenetic 'language' of covalent histone modifications to cancer. Br. J. Cancer 90, 761–769 (2004).
Lachner, M. & Jenuwein, T. The many faces of histone lysine methylation. Curr. Opin. Cell Biol. 14, 286–298 (2002).
Gill, G. SUMO and ubiquitin in the nucleus: different functions, similar mechanisms? Genes Dev. 18, 2046–2059 (2004).
Hassa, P. O., Haenni, S. S., Elser, M. & Hottiger, M. O. Nuclear ADP-ribosylation reactions in mammalian cells: where are we today and where are we going? Microbiol. Mol. Biol. Rev. 70, 789–829 (2006).
Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).
Narlikar, G. J., Fan, H. Y. & Kingston, R. E. Cooperation between complexes that regulate chromatin structure and transcription. Cell 108, 475–487 (2002).
Shi, Y. et al. Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 119, 941–953 (2004).
Brami-Cherrier, K. et al. Parsing molecular and behavioral effects of cocaine in mitogen- and stress-activated protein kinase-1-deficient mice. J. Neurosci. 25, 11444–11454 (2005). Explores the signal transduction cascades, and their effect on downstream chromatin remodelling and associated gene expression, in striatal neurons in response to cocaine. It shows that cocaine causes induction of H4 acetylation, H3 phosphorylation and CREB phosphorylation through MSK1.
Kumar, A. et al. Chromatin remodeling is a key mechanism underlying cocaine-induced plasticity in striatum. Neuron 48, 303–314 (2005). Establishes an important role for chromatin remodelling in the reward responses to cocaine. Also, using chromatin immunoprecipitation assays, it shows that cocaine induces distinct histone modifications and in vivo binding of the transcription factor ΔFOSB at specific gene promoters in the striatum.
Li, J. et al. Dopamine D2-like antagonists induce chromatin remodeling in striatal neurons through cyclic AMP-protein kinase A and NMDA receptor signaling. J. Neurochem. 90, 1117–1131 (2004). Demonstrates that acute administration of antipsychotic drugs to rodents increases global levels of histone acetylation in the striatum and provides evidence for the signal transduction mechanisms that mediate this effect.
Crosio, C., Heitz, E., Allis, C. D., Borrelli, E. & Sassone-Corsi, P. Chromatin remodeling and neuronal response: multiple signaling pathways induce specific histone H3 modifications and early gene expression in hippocampal neurons. J. Cell Sci. 116, 4905–4914 (2003).
Bode, A. M. & Dong, Z. Inducible covalent posttranslational modification of histone H3. Sci. STKE 2005, re4 (2005).
Chawla, S., Vanhoutte, P., Arnold, F. J., Huang, C. L. & Bading, H. Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5. J. Neurochem. 85, 151–159 (2003).
Linseman, D. A. et al. Inactivation of the myocyte enhancer factor-2 repressor histone deacetylase-5 by endogenous Ca2+ //calmodulin-dependent kinase II promotes depolarization-mediated cerebellar granule neuron survival. J. Biol. Chem. 278, 41472–41481 (2003).
Gregoire, S. et al. Control of MEF2 transcriptional activity by coordinated phosphorylation and sumoylation. J. Biol. Chem. 281, 4423–4433 (2006).
Berton, O. & Nestler, E. J. New approaches to antidepressant drug discovery: beyond monoamines. Nature Rev. Neurosci. 7, 137–151 (2006).
Tsankova, N. M., Kumar, A. & Nestler, E. J. Histone modifications at gene promoter regions in rat hippocampus after acute and chronic electroconvulsive seizures. J. Neurosci. 24, 5603–5610 (2004). Outlines a standardized approach to performing chromatin immunoprecipitation assays in rodent brain tissue. It also provides a detailed analysis of several transient and lasting changes in histone modifications after acute and chronic seizure, in correlation with changes in gene expression at the specific gene promoters.
Duman, R. S. Depression: a case of neuronal life and death? Biol. Psychiatry 56, 140–145 (2004).
Nestler, E. J. et al. Neurobiology of depression. Neuron 34, 13–25 (2002).
Duman, R. S. Role of neurotrophic factors in the etiology and treatment of mood disorders. Neuromolecular Med. 5, 11–25 (2004).
Monteggia, L. M. et al. Essential role of brain-derived neurotrophic factor in adult hippocampal function. Proc. Natl Acad. Sci. USA 101, 10827–10832 (2004).
Monteggia, L. M. et al. Brain-derived neurotrophic factor conditional knockouts show gender differences in depression-related behaviors. Biol. Psychiatry 61, 187–197 (2006).
Berton, O. et al. Essential role of BDNF in the mesolimbic dopamine pathway in social defeat stress. Science 311, 864–868 (2006). The authors use chronic social defeat stress as an animal model of depression and demonstrate a crucial role for the neurotrophic factor BDNF in the mesolimbic dopamine pathway in mediating some of the deleterious molecular and behavioural sequelae of this stress paradigm.
Tsankova, N. M. et al. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neurosci. 9, 519–525 (2006). The first study to examine the involvement of chromatin remodelling in an animal model of depression. It reveals robust and lasting in vivo changes in histone modifications, and a role for HDAC5 in chronic social defeat stress and in antidepressant efficacy.
Schroeder, F. A., Lin, C. L., Crusio, W. E. & Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse (in the press).
Lee, M. G., Wynder, C., Schmidt, D. M., McCafferty, D. G. & Shiekhattar, R. Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications. Chem. Biol. 13, 563–567 (2006).
Champagne, F. A., Francis, D. D., Mar, A. & Meaney, M. J. Variations in maternal care in the rat as a mediating influence for the effects of environment on development. Physiol. Behav. 79, 359–371 (2003).
Meaney, M. J. & Szyf, M. Maternal care as a model for experience-dependent chromatin plasticity? Trends Neurosci. 28, 456–463 (2005).
Weaver, I. C. et al. Epigenetic programming by maternal behavior. Nature Neurosci. 7, 847–854 (2004). This important study provides highly novel evidence that the epigenetic state of GR in the hippocampus of rodent offspring, in particular its level of DNA methylation, can be modulated by maternal nurturing behavior in a lasting but reversible manner.
Levenson, J. M. et al. Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J. Biol. Chem. 281, 15763–15773 (2006). Along with reference 69, this study implicates rapid and reversible changes in DNA methylation in synaptic plasticity in the rodent hippocampus, and in the formation of long-term memory. The notion that DNA methylation is subject to dynamic regulation in the adult brain is highly novel and has important implications for our understanding of the epigenetic control of brain function.
Everitt, B. J. & Robbins, T. W. Neural systems of reinforcement for drug addiction: from actions to habits to compulsion. Nature Neurosci. 8, 1481–1489 (2005).
Hyman, S. E., Malenka, R. C. & Nestler, E. J. Neural mechanisms of addiction: the role of reward-related learning and memory. Annu. Rev. Neurosci. 29, 565–598 (2006).
Freeman, W. M. et al. Cocaine-responsive gene expression changes in rat hippocampus. Neuroscience 108, 371–380 (2001).
Freeman, W. M. et al. Changes in rat frontal cortex gene expression following chronic cocaine. Brain Res. Mol. Brain Res. 104, 11–20 (2002).
Kreek, M. J., Bart, G., Lilly, C., LaForge, K. S. & Nielsen, D. A. Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol. Rev. 57, 1–26 (2005).
McClung, C. A. & Nestler, E. J. Regulation of gene expression and cocaine reward by CREB and ΔFosB. Nature Neurosci. 6, 1208–1215 (2003).
McClung, C. A. et al. Regulation of gene expression by chronic morphine and morphine withdrawal in the locus ceruleus and ventral tegmental area. J. Neurosci. 25, 6005–6015 (2005).
Yao, W. D. et al. Identification of PSD-95 as a regulator of dopamine-mediated synaptic and behavioral plasticity. Neuron 41, 625–638 (2004).
Grimm, J. W. et al. Time-dependent increases in brain-derived neurotrophic factor protein levels within the mesolimbic dopamine system after withdrawal from cocaine: implications for incubation of cocaine craving. J. Neurosci. 23, 742–747 (2003).
Colvis, C. M. et al. Epigenetic mechanisms and gene networks in the nervous system. J. Neurosci. 25, 10379–10389 (2005).
Levine, A. A. et al. CREB-binding protein controls response to cocaine by acetylating histones at the fosB promoter in the mouse striatum. Proc. Natl Acad. Sci. USA 102, 19186–19191 (2005). Characterizes the influence of chromatin remodelling on cocaine action in the brain. In particular, it shows that recruitment of CBP to the FosB promoter and the resulting H4 acetylation are essential for normal levels of FosB expression, for accumulation of the transcription factor ΔFOSB, and for normal sensitivity to cocaine.
Bibb, J. A. et al. Effects of chronic exposure to cocaine are regulated by the neuronal protein Cdk5. Nature 410, 376–380 (2001).
Lee, M. P. Genome-wide analysis of epigenetics in cancer. Ann. NY Acad. Sci. 983, 101–109 (2003).
Lee, T. I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).
Impey, S. et al. Defining the CREB regulon: a genome-wide analysis of transcription factor regulatory regions. Cell 119, 1041–1054 (2004). Introduces a novel method of genome-wide analysis of transcription factor binding sites, termed SACO, which combines chromatin immunoprecipitation with long serial analysis of gene expression by direct sequencing rather than by the use of microarray chips.
Kumar, A. et al. Global maps of histone acetylation and gene regulatory networks in the nucleus accumbens after chronic cocaine using chip on chip. Soc. Neurosci. Abstr. 451.4 (2005).
Kumar, A. et al. Transcriptional and post-transcriptional regulation of gene expression in nucleus accumbens associated with chronic stress-induced neuroadaptations in mouse. Soc. Neurosci. Abstr. 191.23 (2006).
Renthal, W. et al. Epigenetic control of cocaine reward by class II histone deacetylases. Soc. Neurosci. Abstr. 294.27 (2006).
Norrholm, S. D. et al. Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5. Neuroscience 116, 19–22 (2003).
Cassel, S. et al. Fluoxetine and cocaine induce the epigenetic factors MeCP2 and MBD1 in adult rat brain. Mol. Pharmacol. 70, 487–492 (2006).
Li, Z. et al. Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repression of transcription. J. Biol. Chem. 279, 54438–54444 (2004).
Korutla, L., Wang, P. J. & Mackler, S. A. The POZ/BTB protein NAC1 interacts with two different histone deacetylases in neuronal-like cultures. J. Neurochem. 94, 786–793 (2005).
Mahadev, K. & Vemuri, M. C. Effect of ethanol on chromatin and nonhistone nuclear proteins in rat brain. Neurochem. Res. 23, 1179–1184 (1998).
Bonsch, D., Lenz, B., Kornhuber, J. & Bleich, S. DNA hypermethylation of the alpha synuclein promoter in patients with alcoholism. Neuroreport 16, 167–170 (2005).
Kim, J. S. & Shukla, S. D. Acute in vivo effect of ethanol (binge drinking) on histone H3 modifications in rat tissues. Alcohol Alcohol. 41, 126–132 (2006).
Bailey, C. H., Kandel, E. R. & Si, K. The persistence of long-term memory: a molecular approach to self-sustaining changes in learning-induced synaptic growth. Neuron 44, 49–57 (2004).
Levenson, J. M. & Sweatt, J. D. Epigenetic mechanisms in memory formation. Nature Rev. Neurosci. 6, 108–118 (2005).
Alarcon, J. M. et al. Chromatin acetylation, memory, and LTP are impaired in CBP+/− mice: a model for the cognitive deficit in Rubinstein–Taybi syndrome and its amelioration. Neuron 42, 947–959 (2004).
Korzus, E., Rosenfeld, M. G. & Mayford, M. CBP histone acetyltransferase activity is a critical component of memory consolidation. Neuron 42, 961–972 (2004).
Levenson, J. M. et al. Regulation of histone acetylation during memory formation in the hippocampus. J. Biol. Chem. 279, 40545–40559 (2004).
Chwang, W. B., O'Riordan, K. J., Levenson, J. M. & Sweatt, J. D. ERK/MAPK regulates hippocampal histone phosphorylation following contextual fear conditioning. Learn. Mem. 13, 322–328 (2006).
Kim, Y. et al. Epigenetic regulation of brain function by Polycomb and Trithorax complexes. Soc. Neurosci. Abstr. 750.5 (2006).
Guan, Z. et al. Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure. Cell 111, 483–493 (2002).
Miller, C. A. & Sweatt, J. D. Covalent modification of DNA regulates memory formation. Neuron 53, 857–869 (2007). Demonstrates rapid changes in the methylation of several memory-related genes (for example, Bdnf, PP1 and reelin) in the hippocampus during contextual fear conditioning. The study, along with reference 35, provides one of the best indications so far that DNA methylation may be rapidly induced and reversed in the adult brain.
Ausio, J., Levin, D. B., De Amorim, G. V., Bakker, S. & Macleod, P. M. Syndromes of disordered chromatin remodeling. Clin. Genet. 64, 83–95 (2003).
Zoghbi, H. Y. MeCP2 dysfunction in humans and mice. J. Child Neurol. 20, 736–740 (2005).
Amir, R. E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999).
Luikenhuis, S., Giacometti, E., Beard, C. F. & Jaenisch, R. Expression of MeCP2 in postmitotic neurons rescues Rett syndrome in mice. Proc. Natl Acad. Sci. USA 101, 6033–6038 (2004).
Dani, V. S. et al. Reduced cortical activity due to a shift in the balance between excitation and inhibition in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 102, 12560–12565 (2005).
Chang, Q., Khare, G., Dani, V., Nelson, S. & Jaenisch, R. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49, 341–348 (2006).
Gemelli, T. et al. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol. Psychiatry 59, 468–476 (2006).
Moretti, P. et al. Learning and memory and synaptic plasticity are impaired in a mouse model of Rett syndrome. J. Neurosci. 26, 319–327 (2006).
Nelson, E. D., Kavalali, E. T. & Monteggia, L. M. MeCP2-dependent transcriptional repression regulates excitatory neurotransmission. Curr. Biol. 16, 710–716 (2006). Characterizes abnormalities in presynaptic excitatory transmission in cultured hippocampal neurons from mice lacking MeCP2. It shows that such abnormalities are not developmental in nature, but rather can be induced in adult neurons by deletion of Mecp2 and, conversely, that the consequences of early gene deletion can be corrected by inhibitors of transcription.
Chen, R. Z., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nature Genet. 27, 327–331 (2001).
McGill, B. E. et al. Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. Proc. Natl Acad. Sci. USA 103, 18267–18272 (2006).
Guy, J., Gan, J., Selfridge, J., Cobb, S. & Bird, A. Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007). Shows that Rett-like symptoms induced in mice as a result of loss of function mutations in MeCP2 can be largely reversed upon correction of the MeCP2 deficit. This supports the notion that it may be possible to treat Rett syndrome in humans even after it has become symptomatic.
Tremolizzo, L. et al. An epigenetic mouse model for molecular and behavioral neuropathologies related to schizophrenia vulnerability. Proc. Natl Acad. Sci. USA 99, 17095–17100 (2002).
Tamminga, C. A. & Holcomb, H. H. Phenotype of schizophrenia: a review and formulation. Mol. Psychiatry 10, 27–39 (2005).
Grayson, D. R. et al. The human reelin gene: transcription factors (+), repressors (−) and the methylation switch (+/−) in schizophrenia. Pharmacol. Ther. 111, 272–286 (2006).
Chen, Y., Sharma, R. P., Costa, R. H., Costa, E. & Grayson, D. R. On the epigenetic regulation of the human reelin promoter. Nucleic Acids Res. 30, 2930–2939 (2002).
Dong, E. et al. Reelin and glutamic acid decarboxylase67 promoter remodeling in an epigenetic methionine-induced mouse model of schizophrenia. Proc. Natl Acad. Sci. USA 102, 12578–12583 (2005). Provides evidence to support their hypothesis that epigenetic abnormalities, specifically, altered methylation of the reelin and Gad67 gene promoters, contribute to the pathophysiology of schizophrenia in a mouse model.
Antun, F. T. et al. The effects of L-methionine (without MAOI) in schizophrenia. J. Psychiatr. Res. 8, 63–71 (1971).
Tremolizzo, L. et al. Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice. Biol. Psychiatry 57, 500–509 (2005).
Cervoni, N. & Szyf, M. Demethylase activity is directed by histone acetylation. J. Biol. Chem. 276, 40778–84077 (2001).
Cervoni, N., Detich, N., Seo, S. B., Chakravarti, D. & Szyf, M. The oncoprotein Set/TAF-1β, an inhibitor of histone acetyltransferase, inhibits active demethylation of DNA, integrating DNA methylation and transcriptional silencing. J. Biol. Chem. 277, 25026–25031 (2002).
Casey, D. E. et al. Effect of divalproex combined with olanzapine or risperidone in patients with an acute exacerbation of schizophrenia. Neuropsychopharmacology 28, 182–192 (2003).
Tsankov, A. M. et al. Communication between levels of transcriptional control improves robustness and adaptivity. Mol. Syst. Biol. 2, 65 (2006). Provides a system-level view of how transcription factors, chromatin regulators, RNA processing and nuclear transport proteins affect gene expression, revealing an elegant architecture for transcriptional control that improves the resilience and responsiveness of the eukaryotic cell.
Hsieh, J. & Gage, F. H. Chromatin remodeling in neural development and plasticity. Curr. Opin. Cell Biol. 17, 664–671 (2005).
Ballas, N. & Mandel, G. The many faces of REST oversee epigenetic programming of neuronal genes. Curr. Opin. Neurobiol. 15, 500–506 (2005).
Kuwabara, T., Hsieh, J., Nakashima, K., Taira, K. & Gage, F. H. A small modulatory dsRNA specifies the fate of adult neural stem cells. Cell 116, 779–793 (2004).
Marin-Husstege, M., Muggironi, M., Liu, A. & Casaccia-Bonnefil, P. Histone deacetylase activity is necessary for oligodendrocyte lineage progression. J. Neurosci. 22, 10333–10345 (2002).
Fan, G. et al. DNA hypomethylation perturbs the function and survival of CNS neurons in postnatal animals. J. Neurosci. 21, 788–797 (2001).
Zhao, X. et al. Mice lacking methyl-CpG binding protein 1 have deficits in adult neurogenesis and hippocampal function. Proc. Natl Acad. Sci. USA 100, 6777–6782 (2003).
Liu, Q. R. et al. Rodent BDNF genes, novel promoters, novel splice variants, and regulation by cocaine. Brain Res. 1067, 1–12 (2006).
Timmusk, T. et al. Multiple promoters direct tissue-specific expression of the rat BDNF gene. Neuron 10, 475–489 (1993).
Tao, X., Finkbeiner, S., Arnold, D. B., Shaywitz, A. J. & Greenberg, M. E. Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20, 709–726 (1998).
Chen, W. G. et al. Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889 (2003).
Zhou, Z. et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255–269 (2006).
Huang, Y., Doherty, J. J. & Dingledine, R. Altered histone acetylation at glutamate receptor 2 and brain-derived neurotrophic factor genes is an early event triggered by status epilepticus. J. Neurosci. 22, 8422–8428 (2002). The first paper to demonstrate regulation of histone acetylation in the adult rat brain. The authors characterize rapid changes in acetylation at the Bdnf and Glur2 promoters in response to chemically induced seizures.
Lim, J. H., Booker, A. B. & Fallon, J. R. Regulating fragile X gene transcription in the brain and beyond. J. Cell Physiol. 205, 170–175 (2005).
Merienne, K., Pannetier, S., Harel-Bellan, A. & Sassone-Corsi, P. Mitogen-regulated RSK2-CBP interaction controls their kinase and acetylase activities. Mol. Cell Biol. 21, 7089–7096 (2001).
Weeber, E. J., Levenson, J. M. & Sweatt, J. D. Molecular genetics of human cognition. Mol. Interv. 2, 376–91, 339 (2002).
Davies, W., Isles, A. R. & Wilkinson, L. S. Imprinted gene expression in the brain. Neurosci. Biobehav. Rev. 29, 421–430 (2005).
Vo, N. & Goodman, R. H. CREB-binding protein and p300 in transcriptional regulation. J. Biol. Chem. 276, 13505–13508 (2001).
Preparation of this review was supported by grants from the National Institute on Drug Abuse and the National Institute of Mental Health.
The authors declare no competing financial interests.
Supplementary information S1 (table)
Tsankova et al., Epigenetic Regulation in Psychiatric Disorders (PDF 215 kb)
Highly basic proteins that comprise the major protein constituents of the nucleus. Octomeric complexes of histones, around which DNA is wrapped, form the nucleosome, the basic building block of chromatin.
The basic building block of chromatin in which 147 base pairs of DNA are wrapped (∼1.65 turns) around a core histone octamer.
The inactivated state of chromatin, in which DNA is not accessible for transcription due to covalent modifications of histones, methylation of the DNA and the binding of numerous repressor proteins.
The activated state of chromatin, in which sections of DNA are accessible to the transcriptional machinery.
Covalent addition of a small protein, called ubiquitin, to many types of proteins. Addition of multiple ubiquitin groups, polyubiquitylation, targets proteins for degradation in the proteasome. By contrast, monoubiquitylation of histones and other regulatory proteins alters their functional properties.
Covalent addition of SUMO, which are small ubiquitin-related modifier proteins, to histones and many other types of regulatory proteins, which alters those proteins' function.
- Nucleosome sliding
The movement of the core histone octamer relative to the DNA, which allows that DNA to be progressively transcribed into RNA.
Protein complex that partly mediates nucleosome sliding in an ATP-dependent manner. The name comes from genetic screens of yeast which identified proteins implicated in mating switching and sucrose non-fermentation. The proteins were later found to regulate nucleosome sliding.
- Histone substitution
A type of chromatin remodelling where histone constituents of the nucleosome can be replaced by other naturally occurring histone variants.
- X-chromosome inactivation
Chromatin remodelling on a very large scale, whereby one of two X chromosomes in all cells of a female organism are inactivated by DNA hypermethylation. Once that chromosome is silenced, it remains inactive for the life of the organism.
- Genetic imprinting
A process where only the maternal or paternal allele of a gene is expressed in the offspring. The other, inactivated allele is transcriptionally silenced through DNA methylation at CpG-rich domains.
- Chromatin immunoprecipitation
(ChIP). A method that enables the identification of histone modifications or transcriptional regulatory proteins at a given gene promoter. In the assay, DNA is crosslinked to nearby proteins by light fixation, the material is sheared, then immunoprecipitated with an antibody to a particular protein of interest, and genes in the final immunoprecipitate are quantified by polymerase chain reaction.
- Immediate-early genes
Genes that are induced rapidly and transiently without the need for new protein synthesis. Many immediate-early genes, such as c-Fos, control the transcription of other genes, and thereby provide the early stages in the control of the production of specific proteins.
- DNA demethylases
Enzymes, not yet molecularly characterized, that demethylate CpG residues in DNA. Active DNA demethylation may also occur through alternative mechanisms such as DNA repair and deamination.
- ChIP on chip
A method that enables a global analysis of genes associated with a particular histone modification or transcriptional regulatory protein. Immunoprecipitated chromatin is analysed on a microarray gene chip, enriched in promoter regions.
Serial analysis of chromatin occupancy, an alternative method to ChIP on chip, is used to obtain a genome-wide appreciation of the genes that bind a particular histone modification or transcriptional regulatory protein. Instead of hybridizing the immunoprecipitated DNA to a microarray, the DNA is directly sequenced.
- Circular dichroism
A form of spectroscopy, involving the differential absorption of left- and right-handed polarized light, used to study the structure of complex molecules.
A commonly used anticonvulsant and antimanic medication. Among many other actions (for example, direct effects on the brains GABA pathways), valproate is a nonspecific inhibitor of class I and class II HDACs.
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Tsankova, N., Renthal, W., Kumar, A. et al. Epigenetic regulation in psychiatric disorders. Nat Rev Neurosci 8, 355–367 (2007). https://doi.org/10.1038/nrn2132
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