DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients

Auta, James; Smith, Robert C.; Dong, Erbao; Tueting, Patricia; Sershen, Henry; Boules, Sylvia; Lajtha, Ábel; Davis, John M.; Guidotti, Alessandro

doi:10.1016/j.schres.2013.07.030

Cited by 61 publications

(55 citation statements)

References 39 publications

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“…These studies are too numerous to describe here in detail. However, it is interesting that several genes that show alterations in brain—for example, RELN and GAD1 —are also reported to differ in peripheral tissues (Aberg and others 2014; Auta and others 2013; Gavin and others 2009). Abnormal methylation status has been reported in blood for several additional candidate genes, such as BDNF (brain-derived neurotrophic factor), 5HTR1A (serotonin 1A receptor), and COMT (catechol-O-methyltransferase) (Carrard and others 2011; Ikegame and others 2013; Kundakovic and others 2015; Walton and others 2014).…”

Section: Epigenetic Mechanisms Of Schizophreniamentioning

confidence: 99%

Epigenetic Basis of Mental Illness

et al. 2016

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Psychiatric disorders are complex multifactorial illnesses involving chronic alterations in neural circuit structure and function as well as likely abnormalities in glial cells. While genetic factors are important in the etiology of most mental disorders, the relatively high rates of discordance among identical twins, particularly for depression and other stress-related syndromes, clearly indicate the importance of additional mechanisms. Environmental factors such as stress are known to play a role in the onset of these illnesses. Exposure to such environmental insults induces stable changes in gene expression, neural circuit function, and ultimately behavior, and these maladaptations appear distinct between developmental versus adult exposures. Increasing evidence indicates that these sustained abnormalities are maintained by epigenetic modifications in specific brain regions. Indeed, transcriptional dysregulation and the aberrant epigenetic regulation that underlies this dysregulation is a unifying theme in psychiatric disorders. Here, we provide a progress report of epigenetic studies of the three major psychiatric syndromes, depression, schizophrenia, and bipolar disorder. We review the literature derived from animal models of these disorders as well as from studies of postmortem brain tissue from human patients. While epigenetic studies of mental illness remain at early stages, understanding how environmental factors recruit the epigenetic machinery within specific brain regions to cause lasting changes in disease susceptibility and pathophysiology is revealing new insight into the etiology and treatment of these conditions.

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Section: Epigenetic Mechanisms Of Schizophreniamentioning

confidence: 99%

Epigenetic Basis of Mental Illness

et al. 2016

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“…Therefore, there can be little doubt that a new generation of epigenetic studies, exploring PVI and other cell-type specific epigenomes in diseased human brain and in preclinical model systems, is likely to provide novel insights into the neurobiology of SCZ and related disease. Furthermore, DNA methylation and histone modification changes at some of the promoters regulating PVI circuitry including REELIN, GAD1 (encoding GAD67 GABA synthesis enzyme) and BDNF (Brain-derived Neurotrophic Factor), not only show epigenetic status in SCZ postmortem brain, were also found in lymphocyte extracts from patients (Aberg, McClay, Nerella, Clark, Kumar, Chen, Khachane, Xie, Hudson, Gao, Harada, Hultman, Sullivan, Magnusson, and van den Oord, 2014; Auta, Smith, Dong, Tueting, Sershen, Boules, Lajtha, Davis, and Guidotti, 2013; Gavin, Kartan, Chase, Jayaraman, and Sharma, 2009; Ikegame, Bundo, Murata, Kasai, Kato, and Iwamoto, 2013). This is interesting because it may provide an opportunity to explore epigenetic alterations in the context of ‘biomarkers’ (defined here as molecular or functional marker for a disease process – SCZ), including coordinated neuronal network synchronizations such as the 40–100 Hz ‘gamma’ oscillations and their cognitive and neuroimaging correlates amenable to exploration in SCZ patients and healthy subjects (Cho, Konecky, and Carter, 2006; Hirano, Oribe, Kanba, Onitsuka, Nestor, and Spencer, 2015; Yoon, Maddock, Rokem, Silver, Minzenberg, Ragland, and Carter, 2010).…”

Section: Epigenetic Regulation In Cortical Interneuronsmentioning

confidence: 99%

Interneuron epigenomes during the critical period of cortical plasticity: Implications for schizophrenia

Morishita

Kundaković

Bicks

et al. 2015

Neurobiology of Learning and Memory

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Schizophrenia, a major psychiatric disorder defined by delusions and hallucinations, among other symptoms, often with onset in early adulthood, is potentially associated with molecular and cellular alterations in parvalbumin-expressing fast spiking interneurons and other constituents of the cortical inhibitory GABAergic circuitry. The underlying mechanisms, including the role of disease-associated risk factors operating in adolescence such as drug abuse and social stressors, remain incompletely understood. Here, we summarize emerging findings from animal models, highlighting the ability of parvalbuminergic interneurons (PVI) to induce, during the juvenile period, long-term plastic changes in prefrontal and visual cortex, thereby altering perception, cognition and behavior in the adult. Of note, molecular alterations in PVI from subjects with schizophrenia, including downregulated expression of a subset of GABAergic genes, have also been found in juvenile stress models of the disorder. Some of the transcriptional alterations observed in schizophrenia postmortem brain could be linked to changes in the epigenetic architecture of GABAergic gene promoters, including dysregulated DNA methylation, histone modification patterns and disruption of promoter-enhancer interactions at site of chromosomal loop formations. Therefore, we predict that, in the not-to-distant future, PVI- and other cell-type specific epigenomic mappings in the animal model and human brain will provide novel insights into the pathophysiology of schizophrenia and related psychotic diseases, including the role of cortical GABAergic circuitry in shaping long-term plasticity and cognitive function of the cerebral cortex.

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“…Analysis of whole-genome biomarker expression in blood and brain samples shows that about 22% of total transcriptome in postmortem brain is expressed at a similar level and pattern in blood elements [80]. Studies comparing gene-expression patterns, epigenetic differences and subcellular organelles in bipolar disorder and schizophrenia have found disease-related changes that are present in both the brain and in peripheral cells [13,20,21,81,82,83,84]. Nonetheless, it is important to follow up these results in human neuronal cells, derived from patient-induced pluripotent stem cells to see which group-related metabolite differences observed in the fibroblasts are present in neuronal cells as well.…”

Section: Discussionmentioning

confidence: 99%

Perturbational Profiling of Metabolites in Patient Fibroblasts Implicates α-Aminoadipate as a Potential Biomarker for Bipolar Disorder

et al. 2016

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Many studies suggest the presence of aberrations in cellular metabolism in bipolar disorder. We studied the metabolome in bipolar disorder to gain insight into cellular pathways that may be dysregulated in bipolar disorder and to discover evidence of novel biomarkers. We measured polar and nonpolar metabolites in fibroblasts from subjects with bipolar I disorder and matched healthy control subjects, under normal conditions and with two physiologic perturbations: low-glucose media and exposure to the stress-mediating hormone dexamethasone. Metabolites that were significantly different between bipolar and control subjects showed distinct separation by principal components analysis methods. The most statistically significant findings were observed in the perturbation experiments. The metabolite with the lowest p value in both the low-glucose and dexamethasone experiments was α-aminoadipate, whose intracellular level was consistently lower in bipolar subjects. Our study implicates α-aminoadipate as a possible biomarker in bipolar disorder that manifests under cellular stress. This is an intriguing finding given the known role of α-aminoadipate in the modulation of kynurenic acid in the brain, especially as abnormal kynurenic acid levels have been implicated in bipolar disorder.

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DNA-methylation gene network dysregulation in peripheral blood lymphocytes of schizophrenia patients

Cited by 61 publications

References 39 publications

Epigenetic Basis of Mental Illness

Epigenetic Basis of Mental Illness

Interneuron epigenomes during the critical period of cortical plasticity: Implications for schizophrenia

Perturbational Profiling of Metabolites in Patient Fibroblasts Implicates α-Aminoadipate as a Potential Biomarker for Bipolar Disorder

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