A Guidotti

University of Illinois at Chicago, Chicago, Illinois, United States

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Publications (506)2489.65 Total impact

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    ABSTRACT: The contribution of epigenetic factors, such as histone acetylation and DNA methylation, to the regulation of alcohol-drinking behavior has been increasingly recognized over the last several years. GADD45b is a protein demonstrated to be involved in DNA demethylation at neurotrophic factor gene promoters, including at brain-derived neurotrophic factor (Bdnf) which has been highly implicated in alcohol-drinking behavior. DNA methyltransferase-1 (Dnmt1), 3a, and 3b, and Gadd45a, b, and g mRNA were measured in the nucleus accumbens (NAc) and ventral tegmental areas of high ethanol (EtOH) consuming C57BL/6J (C57) and low alcohol consuming DBA/2J (DBA) mice using quantitative reverse transcriptase polymerase chain reaction (PCR). In the NAc, GADD45b protein was measured via immunohistochemistry and Bdnf9a mRNA using in situ PCR. Bdnf9a promoter histone H3 acetylated at lysines 9 and 14 (H3K9,K14ac) was measured using chromatin immunoprecipitation, and 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) using methylated DNA immunoprecipitation. Alcohol-drinking behavior was evaluated in Gadd45b haplodeficient (+/−) and null mice (−/−) utilizing drinking-in-the-dark (DID) and 2-bottle free-choice paradigms. C57 mice had lower levels of Gadd45b and g mRNA and GADD45b protein in the NAc relative to the DBA strain. C57 mice had lower NAc shell Bdnf9a mRNA levels, Bdnf9a promoter H3K9,K14ac, and higher Bdnf9a promoter 5HMC and 5MC. Acute EtOH increased GADD45b protein, Bdnf9a mRNA, and histone acetylation and decreased 5HMC in C57 mice. Gadd45b +/− mice displayed higher drinking behavior relative to wild-type littermates in both DID and 2-bottle free-choice paradigms. These data indicate the importance of the DNA demethylation pathway and its interactions with histone posttranslational modifications in alcohol-drinking behavior. Further, we suggest that lower DNA demethylation protein GADD45b levels may affect Bdnf expression possibly leading to altered alcohol-drinking behavior.
    No preview · Article · Feb 2016 · Alcoholism Clinical and Experimental Research

  • No preview · Article · Jan 2016 · Current Neuropharmacology
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    E Dong · P Tueting · F Matrisciano · D R Grayson · A Guidotti
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    ABSTRACT: We have recently reported that mice born from dams stressed during pregnancy (PRS mice), in adulthood, have behavioral deficits reminiscent of behaviors observed in schizophrenia (SZ) and bipolar (BP) disorder patients. Furthermore, we have shown that the frontal cortex (FC) and hippocampus of adult PRS mice, like that of postmortem chronic SZ patients, are characterized by increases in DNA-methyltransferase 1 (DNMT1), ten-eleven methylcytosine dioxygenase 1 (TET1) and exhibit an enrichment of 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) at neocortical GABAergic and glutamatergic gene promoters. Here, we show that the behavioral deficits and the increased 5MC and 5HMC at glutamic acid decarboxylase 67 (Gad1), reelin (Reln) and brain-derived neurotrophic factor (Bdnf) promoters and the reduced expression of the messenger RNAs (mRNAs) and proteins corresponding to these genes in FC of adult PRS mice is reversed by treatment with clozapine (5 mg kg(-1) twice a day for 5 days) but not by haloperidol (1 mg kg(-1) twice a day for 5 days). Interestingly, clozapine had no effect on either the behavior, promoter methylation or the expression of these mRNAs and proteins when administered to offspring of nonstressed pregnant mice. Clozapine, but not haloperidol, reduced the elevated levels of DNMT1 and TET1, as well as the elevated levels of DNMT1 binding to Gad1, Reln and Bdnf promoters in PRS mice suggesting that clozapine, unlike haloperidol, may limit DNA methylation by interfering with DNA methylation dynamics. We conclude that the PRS mouse model may be useful preclinically in screening for the potential efficacy of antipsychotic drugs acting on altered epigenetic mechanisms. Furthermore, PRS mice may be invaluable for understanding the etiopathogenesis of SZ and BP disorder and for predicting treatment responses at early stages of the illness allowing for early detection and remedial intervention.
    Preview · Article · Jan 2016 · Translational Psychiatry
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    ABSTRACT: Schizophrenic patients have a high rate of smoking and cognitive deficits which may be related to a decreased number or responsiveness of nicotinic receptors in their brains. Varenicline is a partial nicotinic agonist which is effective as an antismoking drug in cigarette smokers, although concerns have been raised about potential psychiatric side-effects. We conducted a double-blind placebo controlled study in 87 schizophrenic smokers to evaluate the effects of varenicline (2 mg/day) on measures of smoking, cognition, psychiatric symptoms, and side-effects in schizophrenic patients who were cigarette smokers. Varenicline significantly decreased cotinine levels (P<0.001), and other objective and subjective measures of smoking (P < .01), and responses on a smoking urges scale (P = .02), more than placebo. Varenicline did not improve scores on a cognitive battery designed to test the effect of drugs on cognitive performance in schizophrenia (the MATRICS battery), either in overall MATRICS battery Composite or individual Domain scores, more than placebo. There were no significant differences between varenicline vs. placebo effects on total symptom scores on psychiatric rating scales, PANSS, SANS, or Calgary Depression scales, and there were no significant drug effects in any of these scales sub-scores when we used Benjamin-Hochberg corrected significance levels (α = .05). Varenicline patients did not show greater side-effects than placebo treated patients at any time point when controlled for baseline side-effect scores. Our study supports the use of varenicline as a safe drug for smoking reduction in schizophrenia but not as a cognitive enhancer.
    Preview · Article · Jan 2016 · PLoS ONE
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    ABSTRACT: The term epigenetic commonly refers to stable, environment-depending changes in genes expression that occur without altering the underlying DNA sequence. Epigenetic mechanisms are fundamental for normal development and maintenance of tissue-specifi c gene expression. Abnormalities in epigenetic processes can lead to abnormal gene function and the development of diseases. Recent evidences suggest that several diseases and behavioral disorders result from defects in gene function. Cancer, and other diseases such as autoimmune disease, asthma, type 2 diabetes, metabolic disorders, neuropsychiatric disorders, autism, display aberrant gene expression. A number of compounds targeting enzymes involved in histone acetylation, histone methylation, and DNA methylation have been developed as epigenetic drugs, with some efficacy shown in hematological malignancies and solid tumors. Recently researchers are focusing on finding new epigenetic targets for the development of new molecules for the treatment of different CNS disorders such as autism and schizophrenia targeting specific enzymes that play an important role in gene expression and function.
    No preview · Article · Jan 2016 · Neuromethods
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    ABSTRACT: Maternal infection during pregnancy increases the risk of neurodevelopmental disorders in the offspring. In addition to its influence on other neuronal systems, this early-life environmental adversity has been shown to negatively affect cortical γ-aminobutyric acid (GABA) functions in adult life, including impaired prefrontal expression of enzymes required for GABA synthesis. The underlying molecular processes, however, remain largely unknown. In the present study, we explored whether epigenetic modifications represent a mechanism whereby maternal infection during pregnancy can induce such GABAergic impairments in the offspring. We used an established mouse model of prenatal immune challenge that is based on maternal treatment with the viral mimetic poly(I:C). We found that prenatal immune activation increased prefrontal levels of 5-methylated cytosines (5 mC) and 5-hydroxymethylated cytosines (5 hmC) in the promoter region of GAD1, which encodes the 67-kDa isoform of the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD67). The early-life challenge also increased 5 mC levels at the promoter region of GAD2, which encodes the 65-kDa GAD isoform (GAD65). These effects were accompanied by elevated GAD1 and GAD2 promoter binding of methyl CpG-binding protein 2 (MeCP2) and by reduced GAD67 and GAD65 mRNA expression. Moreover, the epigenetic modifications at the GAD1 promoter correlated with prenatal infection-induced impairments in working memory and social interaction. Our study thus highlights that hypermethylation of GAD1 and GAD2 promoters may be an important molecular mechanism linking prenatal infection to presynaptic GABAergic impairments and associated behavioral and cognitive abnormalities in the offspring.
    Full-text · Article · Nov 2015 · Epigenetics: official journal of the DNA Methylation Society
  • Dennis R Grayson · Alessandro Guidotti
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    ABSTRACT: Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is characterized by a wide range of cognitive and behavioral abnormalities. Genetic research has identified large numbers of genes that contribute to ASD phenotypes. There is compelling evidence that environmental factors contribute to ASD through influences that differentially impact the brain through epigenetic mechanisms. Both genetic mutations and epigenetic influences alter gene expression in different cell types of the brain. Mutations impact the expression of large numbers of genes and also have downstream consequences depending on specific pathways associated with the mutation. Environmental factors impact the expression of sets of genes by altering methylation/hydroxymethylation patterns, local histone modification patterns and chromatin remodeling. Herein, we discuss recent developments in the research of ASD with a focus on epigenetic pathways as a complement to current genetic screening.
    No preview · Article · Nov 2015 · Epigenomics
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    ABSTRACT: In nondividing neurons examine the role of Gadd45b in active 5-methylcytosine (5MC) and 5-hydroxymethylcytosine (5HMC) removal at a gene promoter highly implicated in mental illnesses and cognition, Bdnf. Mouse primary cortical neuronal cultures with and without Gadd45b siRNA transfection were treated with N-methyl-d-aspartate (NMDA). Expression changes of genes reportedly involved in DNA demethylation, Bdnf mRNA and protein and 5MC and 5HMC at Bdnf promoters were measured. Gadd45b siRNA transfection in neurons abolishes the NMDA-induced increase in Bdnf IXa mRNA and reductions in 5MC and 5HMC at the Bdnf IXa promoter. These results contribute to our understanding of DNA demethylation mechanisms in neurons, and its role in regulating NMDA responsive genes implicated in mental illnesses.
    Full-text · Article · Jun 2015 · Epigenomics
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    Full-text · Conference Paper · May 2015
  • E Dong · W B Ruzicka · D R Grayson · A Guidotti
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    ABSTRACT: The down regulation of glutamic acid decarboxylase67 (GAD1), reelin (RELN), and BDNF expression in brain of schizophrenia (SZ) and bipolar (BP) disorder patients is associated with overexpression of DNA methyltransferase1 (DNMT1) and ten-eleven translocase methylcytosine dioxygenase1 (TET1). DNMT1 and TET1 belong to families of enzymes that methylate and hydroxymethylate cytosines located proximal to and within cytosine phosphodiester guanine (CpG) islands of many gene promoters, respectively. Altered promoter methylation may be one mechanism underlying the down-regulation of GABAergic and glutamatergic gene expression. However, recent reports suggest that both DNMT1 and TET1 directly bind to unmethylated CpG rich promoters through their respective Zinc Finger (ZF-CXXC) domains. We report here, that the binding of DNMT1 to GABAergic (GAD1, RELN) and glutamatergic (BDNF-IX) promoters is increased in SZ and BP disorder patients and this increase does not necessarily correlate with enrichment in promoter methylation. The increased DNMT1 binding to these promoter regions is detected in the cortex but not in the cerebellum of SZ and BP disorder patients, suggesting a brain region and neuron specific dependent mechanism. Increased binding of DNMT1 positively correlates with increased expression of DNMT1 and with increased binding of MBD2. In contrast, the binding of TET1 to RELN, GAD1 and BDNF-IX promoters failed to change. These data are consistent with the hypothesis that the down-regulation of specific GABAergic and glutamatergic genes in SZ and BP disorder patients may be mediated, at least in part, by a brain region specific and neuronal-activity dependent DNMT1 action that is likely independent of its DNA methylation activity. Copyright © 2014. Published by Elsevier B.V.
    No preview · Article · Dec 2014 · Schizophrenia Research
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    Alessandro Guidotti · Erbo Dong · Patricia Tueting · Dennis R Grayson
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    ABSTRACT: Based on postmortem brain studies, our overarching epigenetic hypothesis is that chronic schizophrenia (SZ) is a psychopathological condition involving dysregulation of the dynamic equilibrium among DNA methylation/demethylation network components and the expression of SZ target genes, including GABAergic and glutamatergic genes. SZ has a natural course, starting with a prodromal phase, a first episode that occurs in adolescents or in young adults, and later deterioration over the adult years. Hence, the epigenetic status at each neurodevelopmental stage of the disease cannot be studied just in postmortem brain of chronic SZ patients, but requires the use of neurodevelopmental animal models. We have directed the focus of our research toward studying the epigenetic signature of the SZ brain in the offspring of dams stressed during pregnancy (PRS mice). Adult PRS mice have behavioral deficits reminiscent of behaviors observed in psychotic patients. The adult PRS brain, like that of postmortem chronic SZ patients, is characterized by a significant increase in DNA methyltransferase 1, Tet methylcytosine dioxygenase 1 (TET1), 5-methylcytosine, and 5-hydroxymethylcytosine at SZ candidate gene promoters and a reduction in the expression of glutamatergic and GABAergic genes. In PRS mice, measurements of epigenetic biomarkers for SZ can be assessed at different stages of development with the goal of further elucidating the pathophysiology of this disease and predicting treatment responses at specific stages of the illness, with particular attention to early detection and possibly early intervention.
    Full-text · Article · Nov 2014 · Progress in molecular biology and translational science

  • No preview · Article · Oct 2014 · European Neuropsychopharmacology
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    Alessandro Guidotti · Dennis R Grayson
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    ABSTRACT: Schizophrenia (SZ) and bipolar disorder (BPD) patients show a downregulation of GAD67, reelin (RELN), brain-derived neurotrophic factor (BDNF), and other genes expressed in telencephalic GABAergic and glutamatergic neurons. This downregulation is associated with the enrichment of 5-methylcytosine and 5-hydroxymethylcytosine proximally at gene regulatory domains at the respective genes. A pharmacological strategy to reduce promoter hypermethylation and to induce a more permissive chromatin conformation is to administer drugs, such as the histone deacetylase (HDAC) inhibitor valproate (VPA), that facilitate chromatin remodeling. Studies in mouse models of SZ indicate that clozapine induces DNA demethylation at relevant promoters, and that this action is potentiated by VPA. By activating DNA demethylation, clozapine or its derivatives with VPA or other more potent and selective HDAC inhibitors may be a promising treatment strategy to correct the gene expression deficits detected in postmortem brain of SZ and BPD patients.
    Full-text · Article · Sep 2014 · Dialogues in clinical neuroscience
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    Adrian Zhubi · Edwin H Cook · Alessandro Guidotti · Dennis R Grayson
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    ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social interactions, language deficits, as well as restrictive or repetitive behaviors. ASD is clinically heterogeneous with a complex etiopathogenesis which may be conceptualized as a dynamic interplay between heterogeneous environmental cues and predisposing genetic factors involving complex epigenetic mechanisms. Inherited and de novo copy number variants provide novel information regarding genes contributing to ASD. Epigenetic marks are stable, yet potentially reversible, chromatin modifications that alter gene expression profiles by locally changing the degree of nucleosomal compaction, thereby opening or closing promoter access to the transcriptional machinery. Here, we review progress on studies designed to provide a better understanding of how epigenetic mechanisms impact transcriptional programs operative in the brain that contribute to ASD.
    Full-text · Article · Aug 2014 · International Review of Neurobiology
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    ABSTRACT: Background Prenatal stress is considered a risk factor for several neurodevelopmental disorders including schizophrenia (SZ). An animal model involving restraint stress of pregnant mice suggests that prenatal stress (PRS) induces epigenetic changes in specific GABAergic and glutamatergic genes likely to be implicated in SZ including the gene for brain derived neurotrophic factor (BDNF). Methods Studying adult offspring of pregnant mice subjected to PRS, we explored the long-term effects of PRS on behavior and on the expression of key chromatin remodeling factors including DNA methyltransferase 1 (DNMT1), ten-eleven translocation hydroxylases (TETs), methyl CpG binding protein 2 (MeCP2), histone deacetylases (HDACs), histone methyltransferases (MLL1, SETD1, G9a and EZH1) and demethylase (LSD1) in the frontal cortex (FC) and hippocampus (HP). We also measured the expression of BDNF. Results Adult PRS offspring demonstrate behavioral abnormalities suggestive of SZ and molecular changes similar to SZ postmortem brain: a significant increase in DNMT1 and TET1 in the FC and HP but not in cerebellum, no changes in HDACs, histone methytransferases/demethylases or MeCP2, and a significant decrease in BDNF mRNA variants. The decrease of the corresponding BDNF transcript level was accompanied by an enrichment of 5-methylcytosine and 5-hydroxymethylcytosine at Bdnf gene regulatory regions. In addition, the expression of BDNF transcripts (IV and IX) positively correlated with social approach in both PRS and non-stressed mice. Conclusions Since patients with psychosis and PRS mice show similar epigenetic signature, PRS offspring may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in SZ patients.
    Full-text · Article · Aug 2014 · Biological Psychiatry
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    Roberto Carlos Agis-Balboa · Alessandro Guidotti · Graziano Pinna
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    ABSTRACT: Rationale The implications of the neurosteroid 3α-hydroxy-5α-pregnan-20-one [allopregnanolone (Allo)] in neuropsychiatric disorders have been highlighted in several recent clinical investigations. For instance, Allo levels are decreased in the cerebrospinal fluid (CSF) of patients with posttraumatic stress disorder (PTSD) and major unipolar depression. Neurosteroidogenic antidepressants [i.e., selective brain steroidogenic stimulants (SBSSs)], including fluoxetine and analogs, correct this decrease in a manner that correlates with improved depressive symptoms. Allo positively and allosterically modulatesGABAaction at postsynaptic and extrasynaptic GABAA receptors. It is synthesized in both the human and rodent brain cortices by principal glutamatergic pyramidal neurons from progesterone by the sequential action of 5α-reductase type I (5α-RI), which is the rate-limiting step enzyme in Allo biosynthesis, and 3α-hydroxysteroid dehydrogenase (3α-HSD), which converts 5α-dehydroprogesterone into Allo.
    Full-text · Article · Apr 2014 · Psychopharmacology
  • A Guidotti · J Auta · Jm Davis · E Dong · Dp Gavin · Dr Grayson · Rp Sharma · Rc Smith · P Tueting · A Zhubi
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    ABSTRACT: Abstract Schizophrenia (SZ) is a heritable, non-mendelian, neurodevelopmental disorder in which epigenetic dysregulation of the brain genome plays a fundamental role in mediating the clinical manifestations and course of the disease. We recently reported that two enzymes that belong to the dynamic DNA-methylation/demethylation network -DNMT (DNA-methyltransferase) and TET (5-hydroxycytosine translocator)- are abnormally increased in cortico-limbic structures of SZ post-mortem brain suggesting a causal relationship between clinical manifestations of SZ and changes in DNA methylation and in the expression of SZ candidate genes (e.g., brain derived neurotrophic factor [BDNF], glucocorticoid receptor [GCR], glutamic acid decarboxylase67 [GAD67], reelin). Because the clinical manifestations of SZ typically begin with a prodrome followed by a first episode in adolescence with subsequent deterioration, it is obvious that the natural history of this disease cannot be studied only in post-mortem brain. Hence, the focus is currently shifting towards the feasibility of studying epigenetic molecular signatures of SZ in blood cells. Initial studies show a significant enrichment of epigenetic changes in lymphocytes in gene networks directly relevant to psychiatric disorders. Furthermore, the expression of DNA-methylating/demethylating enzymes and SZ candidate genes such as BDNF and GCR are altered in the same direction in both brain and blood lymphocytes. The coincidence of these changes in lymphocytes and brain supports the hypothesis that common environmental or genetic risk factors are operative in altering the epigenetic components involved in orchestrating transcription of specific genes in brain and peripheral tissues. The identification of DNA-methylation signatures for SZ in peripheral blood cells of subjects with genetic and clinical high risk would clearly have potential for the diagnosis of SZ early in its course and would be invaluable for initiating early intervention and individualized treatment plans.
    No preview · Article · Apr 2014 · Journal of neurogenetics
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    A Zhubi · Y Chen · E Dong · E H Cook · A Guidotti · D R Grayson
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    ABSTRACT: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by symptoms related to altered social interactions/communication and restricted and repetitive behaviors. In addition to genetic risk, epigenetic mechanisms (which include DNA methylation/demethylation) are thought to be important in the etiopathogenesis of ASD. We studied epigenetic mechanisms underlying the transcriptional regulation of candidate genes in cerebella of ASD patients, including the binding of MeCP2 (methyl CpG binding protein-2) to the glutamic acid decarboxylase 67 (GAD1), glutamic acid decarboxylase 65 (GAD2), and Reelin (RELN) promoters and gene bodies. Moreover, we performed methyl DNA immunoprecipitation (MeDIP) and hydroxymethyl DNA immunoprecipitation (hMeDIP) to measure total 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the same regions of these genes. The enrichment of 5-hmC and decrease in 5-mC at the GAD1 or RELN promoters detected by 5-hmC and 5-mC antibodies was confirmed by Tet-assisted bisulfite (TAB) pyrosequencing. The results showed a marked and significant increase in MeCP2 binding to the promoter regions of GAD1 and RELN, but not to the corresponding gene body regions in cerebellar cortex of ASD patients. Moreover, we detected a significant increase in TET1 expression and an enrichment in the level of 5-hmC, but not 5-mC, at the promoters of GAD1 and RELN in ASD when compared with CON. Moreover, there was increased TET1 binding to these promoter regions. These data are consistent with the hypothesis that an increase of 5-hmC (relative to 5-mC) at specific gene domains enhances the binding of MeCP2 to 5-hmC and reduces expression of the corresponding target genes in ASD cerebella.
    Full-text · Article · Jan 2014 · Translational Psychiatry
  • Dennis R. Grayson · Alessandro Guidotti
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    ABSTRACT: Individuals with psychosis, including schizophrenia (SZ) and bipolar disorder patients (BP) with psychosis (BP+), express a complex symptomatology characterized by core symptoms that include positive and negative symptoms, as well as cognitive impairment. Autism spectrum disorders (ASD) are characterized by impaired social interactions, altered verbal and non-verbal communications, and repetitive or stereotyped behaviors. Although each disorder has a unique morbidity, age of onset, temporal progression, and responsiveness to pharmacological therapy, there are some shared features with respect to symptomatology that suggest common or overlapping endophenotypes. Postmortem studies of human SZ and BP+brains indicate that there are considerable alterations in the transcriptome of a variety of cortical and limbic structures which, in turn, likely reflect widespread changes in the epigenome. mRNA profiling studies show expression levels that are both up- and/or downregulated in inhibitory GABAergic interneurons, excitatory (glutamatergic) pyramidal neurons, and glia at distinct stages of adolescent maturation and in the adult compared with non-psychiatric subjects (NPS). Alterations in the transcriptome and the epigenome have also been demonstrated in multiple types of neurons and brain regions in ASD, as well as in psychosis. Major depressive disorder (MDD) and suicide completers may also exhibit distinct and overlapping alterations in the epigenome. Many of the symptomatic phenotypes associated with these complex psychiatric disorders are likely the consequence of early-life stressors that occur during prenatal or early-life neurodevelopment. The establishment and maintenance of CpG site methylation are essential during central nervous system maturation and neuronal differentiation. We propose that these DNA modifications represent interconvertible epigenetic states that are context dependent and likely associated with early developmental stress. Whereas CpG methylation is linked with transcriptional downregulation, the role of hydroxymethylation in transcriptional regulation is less clear. Studies also show that CpG binding by methyl-CpG-binding domain proteins acts to both facilitate and antagonize repressed chromatin. DNA-modifying proteins, such as DNMT1 and TET1, also bind CpGs independent of their catalytic function. In addition, both DNMT1 and MeCP2 are more abundant in GABAergic cortical neurons and hippocampal neurons, suggesting the possibility that inhibitory interneurons may differ in how they regulate gene expression as compared with excitatory neurons. Recent experimental observations raise the possibility that neuron-specific targets may be differentially exploited for pharmacological intervention in treating selective endophentoypes associated with psychiatric disorders. There is also widespread interest in understanding whether genome-wide methylation (methylomic) biomarkers present in blood might be useful in predicting BP+, SZ, BP, MDD, ASD, suicide, and responsiveness to specific psychiatric medications.
    No preview · Chapter · Jan 2014
  • J Auta · R C Smith · E Dong · P Tueting · H Sershen · S Boules · A Lajtha · J Davis · A Guidotti
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    ABSTRACT: The epigenetic dysregulation of the brain genome associated with the clinical manifestations of schizophrenia (SZ) includes altered DNA promoter methylation of several candidate genes. We and others have reported that two enzymes that belong to the DNA-methylation/demethylation network pathways-DNMT1 (DNA-methyltransferase) and ten-eleven translocator-1(TET1) methylcytosine deoxygenase are abnormally increased in corticolimbic structures of SZ postmortem brain. The objective of this study was to investigate whether the expression of these components of the DNA-methylation-demethylation pathways known to be altered in the brain of SZ patients are also altered in peripheral blood lymphocytes (PBL). The data show that increases in DNMT1 and TET1 and in glucocorticoid receptor (GCortR) and brain derived neurotrophic factor (BDNF) mRNAs in PBL of SZ patients are comparable to those reported in the brain of SZ patients. The finding that the expressions of DNMT1 and TET1 are increased and SZ candidate genes such as BDNF and GCortR are altered in the same direction in both the brain and PBL together with recent studies showing highly correlated patterns of DNA methylation across the brain and blood, support the hypothesis that a common epigenetic dysregulation may be operative in the brain and peripheral tissues of SZ patients.
    No preview · Article · Aug 2013 · Schizophrenia Research

Publication Stats

26k Citations
2,489.65 Total Impact Points


  • 1996-2016
    • University of Illinois at Chicago
      • Department of Psychiatry (Chicago)
      Chicago, Illinois, United States
  • 2010
    • University of Chicago
      Chicago, Illinois, United States
  • 1995-2006
    • Nathan Kline Institute
      Orangeburg, New York, United States
    • Louisiana State University Health Sciences Center New Orleans
      • Department of Pharmacology and Experimental Therapeutics
      New Orleans, Louisiana, United States
  • 1986-2006
    • Georgetown University
      • • Fidia-Georgetown Institute for the Neurosciences
      • • Department of Medicine
      • • Department of Biochemistry and Molecular and Cellular Biology
      Washington, Washington, D.C., United States
  • 1998
    • University of Groningen
      • Department of Medicinal Chemistry
      Groningen, Groningen, Netherlands
  • 1997
    • University of Santiago de Compostela
      • Department of Morphological Sciences
      Santiago, Galicia, Spain
  • 1992
    • The Neurosciences Institute
      La Jolla, California, United States
  • 1990
    • Universität Heidelberg
      • Center for Molecular Biology (ZMBH)
      Heidelburg, Baden-Württemberg, Germany
  • 1989
    • National Institute on Alcohol Abuse and Alcoholism
      Роквилл, Maryland, United States
  • 1985
    • Max Planck Institute for Biophysical Chemistry
      Göttingen, Lower Saxony, Germany
  • 1974-1985
    • St. Elizabeth Hospital
      Louisiana, United States
  • 1973-1984
    • National Institute of Mental Health (NIMH)
      베서스다, Maryland, United States
  • 1977-1983
    • College of Saint Elizabeth
      Washington, Washington, D.C., United States
  • 1975-1983
    • District of Columbia Department of Mental Health
      Washington, Washington, D.C., United States
    • National Heart, Lung, and Blood Institute
      Maryland, United States
  • 1982
    • Rutgers New Jersey Medical School
      Newark, New Jersey, United States
  • 1972
    • Università degli studi di Cagliari
      Cagliari, Sardinia, Italy
  • 1964-1971
    • University of Florence
      • Dipartimento di Neuroscienze, Psicologia, Area del Farmaco e Salute del Bambino
      Florens, Tuscany, Italy