Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia

Kano, Shin-ichi; Colantuoni, Carlo; Han, Fangxu; Zhou, Zhifeng; Yuan, Qiaoping; Wilson, Ana; Takayanagi, Yoichiro; Lee, Y; Rapoport, Judith L.; Eaton, William W.; Cascella, Nicola G.; Ji, Hongkai; Goldman, David; Sawa, Akira

doi:10.1038/mp.2012.120

Cited by 79 publications

(90 citation statements)

References 10 publications

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“…63,64 Additionally, a recent study of olfactory cells with neuronal phenotype revealed a specific epigenetic regulation of genes that code for enzymes of phase II detoxification, which includes the antioxidant response, in cells from patients with schizophrenia. 65 All together, these results indicate that oxidation might be a shared trait across tissues from schizophrenia patients and might lead to epigenetic imprinting and profound changes in cell physiology.…”

Section: Discussionmentioning

confidence: 94%

Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients

Fournier¹,

Ferrari

Baumann

et al. 2014

Schizophrenia Bulletin

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Because increasing evidence point to the convergence of environmental and genetic risk factors to drive redox dysregulation in schizophrenia, we aim to clarify whether the metabolic anomalies associated with early psychosis reflect an adaptation to oxidative stress. Metabolomic profiling was performed to characterize the response to oxidative stress in fibroblasts from control individuals (n = 20) and early psychosis patients (n = 30), and in all, 282 metabolites were identified. In addition to the expected redox/ antioxidant response, oxidative stress induced a decrease of lysolipid levels in fibroblasts from healthy controls that were largely muted in fibroblasts from patients. Most notably, fibroblasts from patients showed disrupted extracellular matrix-and arginine-related metabolism after oxidative stress, indicating impairments beyond the redox system. Plasma membrane and extracellular matrix, 2 regulators of neuronal activity and plasticity, appeared as particularly susceptible to oxidative stress and thus provide novel mechanistic insights for pathophysiological understanding of early stages of psychosis. Statistically, antipsychotic medication at the time of biopsy was not accounting for these anomalies in the metabolism of patients' fibroblasts, indicating that they might be intrinsic to the disease. Although these results are preliminary and should be confirmed in a larger group of patients, they nevertheless indicate that the metabolic signature of reactivity to oxidative stress may provide reliable early markers of psychosis. Developing protective measures aimed at normalizing the disrupted pathways should prevent the pathological consequences of environmental stressors.

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Section: Discussionmentioning

confidence: 94%

Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients

Fournier¹,

Ferrari

Baumann

et al. 2014

Schizophrenia Bulletin

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show abstract

“…Genomewide profiling of histone methylation and gene expression in neuronal olfactory cells collected by nasal biopsy in SCZ patients and control subjects identified ~500 genes with altered expression or histone methylation in SCZ. Among these, 72 genes (e.g., DAAM2) were dysregulated due to altered levels of H3K4 me3 or H3K27 me3 at the promoter regions of corresponding genes [101]. Other studies found an increased level of H3K9 me2 , which in general represses gene expression, correlated with increased expression of G9a, SETDB1 and GLP genes (which act as methyltranferases for H3K9 me2 modifications) in postmortem brains and/or lymphocytes of SCZ patients [102,103].…”

Section: Histone Methylation and Psychotic Disordersmentioning

confidence: 98%

An Update on the Epigenetics of Psychotic Diseases and Autism

2015

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The examination of potential roles of epigenetic alterations in the pathogenesis of psychotic diseases have become an essential alternative in recent years as genetic studies alone are yet to uncover major gene(s) for psychosis. Here, we describe the current state of knowledge from the gene-specific and genome-wide studies of postmortem brain and blood cells indicating that aberrant DNA methylation, histone modifications and dysregulation of micro-RNAs are linked to the pathogenesis of mental diseases. There is also strong evidence supporting that all classes of psychiatric drugs modulate diverse features of the epigenome. While comprehensive environmental and genetic/epigenetic studies are uncovering the origins, and the key genes/pathways affected in psychotic diseases, characterizing the epigenetic effects of psychiatric drugs may help to design novel therapies in psychiatry.

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“…R. Soc. B 369: 20130514 from a biopsy of the olfactory epithelium of four subjects with schizophrenia and four matched controls [98]. Again, hundreds of loci showed H3K4 methylation changes in the disease cases, and at least 72 genes, some of which were of relevance for oxidative stress, metabolism and cellular (incl.…”

Section: Mouse Models For Genetic Disorders Associated With H3k4 Methmentioning

confidence: 99%

Regulation of histone H3K4 methylation in brain development and disease

Shen

Shulha

Weng

et al. 2014

Phil. Trans. R. Soc. B

126

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The growing list of mutations implicated in monogenic disorders of the developing brain includes at least seven genes ( ARX, CUL4B, KDM5A, KDM5C, KMT2A, KMT2C, KMT2D ) with loss-of-function mutations affecting proper regulation of histone H3 lysine 4 methylation, a chromatin mark which on a genome-wide scale is broadly associated with active gene expression, with its mono-, di- and trimethylated forms differentially enriched at promoter and enhancer and other regulatory sequences. In addition to these rare genetic syndromes, dysregulated H3K4 methylation could also play a role in the pathophysiology of some cases diagnosed with autism or schizophrenia, two conditions which on a genome-wide scale are associated with H3K4 methylation changes at hundreds of loci in a subject-specific manner. Importantly, the reported alterations for some of the diseased brain specimens included a widespread broadening of H3K4 methylation profiles at gene promoters, a process that could be regulated by the UpSET(KMT2E/MLL5)-histone deacetylase complex. Furthermore, preclinical studies identified maternal immune activation, parental care and monoaminergic drugs as environmental determinants for brain-specific H3K4 methylation. These novel insights into the epigenetic risk architectures of neurodevelopmental disease will be highly relevant for efforts aimed at improved prevention and treatment of autism and psychosis spectrum disorders.

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Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia

Cited by 79 publications

References 10 publications

Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients

Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients

An Update on the Epigenetics of Psychotic Diseases and Autism

Regulation of histone H3K4 methylation in brain development and disease

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