Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Co-expression network analysis from genes involved with neural-differentiation shows specific pattern in patients with schizophrenia

ABSTRACT: Schizophrenia is a severe and debilitating neuropsychiatric disorder with the involvement of genetic and environmental factors contributing to its pathogenesis. The specific role of the brain cell types in the disease remains uncovered due to the difficulties in accessing diseased tissue. This study analysed molecular alterations in human induced pluripotent stem cells derived from fibroblasts from control subject and individual with schizophrenia and further differentiated to neuron to identify genes relevant for the development of schizophrenia. We identified 228 genes that are involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. These genes were analysed in expression microarrays of post-mortem brain tissue (frontal cortex) of additional patients with schizophrenia and normal individuals revealing only six common genes: CACNA1E, CEBPB, DUX4, EDNRA, SPHK1 and SPRY4. Furthermore, a co-expression network analysis of the 228 genes revealed a non-conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation as involved with schizophrenia. This study supports the relevance of using cellular approaches to dissect molecular aspects of neurogenesis with impact in the schizophrenic brain. Biopsies of primary human fibroblasts from a 48-year-old woman with DSM-IVTR schizophrenia defined as treatment-resistant under clozapine treatment (SZCP) were collected in parallel with a control subject (CON) negative for any major lifetime DSM-IVTR diagnosis. Fibroblasts underwent primary culture procedures to generate hiPSCs and were subsequently differentiated into neurons (NPC). Samples generation and culture conditions are described in Paulsen et al. (2011). Five replicates of expression microarray experiments using a reference design, where test sample (NPC) is derived from reference sample (hiPSC).

ORGANISM(S): Homo sapiens

SUBMITTER: Renato Puga

PROVIDER: E-GEOD-62105 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Epigenetics describes mechanisms via which the environment can act on the genome, including DNA methylation of promoter regions of genes. This could be a way that environmental risk factors could affect neurodevelopment in individuals at risk for schizophrenia. Patient-derived cells provide a means whereby epigenetics and gene-environment interactions might be investigated. Induced pluripotent stem cells (iPS cells) present an attractive patient-derived cellular model because they can be differentiated into cell types of interest in schizophrenia. In this study the influence of the reprogramming process on schizophrenia-associated DNA methylation was investigated through genome-wide DNA methylation profiling and gene expression of patient-derived iPS cells and the fibroblasts from which they were derived. Olfactory neurosphere-derived cells (ONS cells) from the same patients were also profiled to provide a window on epigenetic regulation in three distinct cell types. Patient-derived cell were compared to cells derived from healthy controls to identify differences in DNA methylation and gene expression associated with schizophrenia in three cell types. The main finding is that iPS cells, prior to neuronal differentiation, demonstrated significant schizophrenia-associated differences in DNA methylation. This is in contrast to the fibroblasts from which they were derived, which show lesser schizophrenia-associated differences in DNA methylation. Like iPS cells, ONS cells showed robust significant schizophrenia-associated differences in DNA methylation. Notably, the schizophrenia-associated differences in DNA methylation were unique for each cell type, with little overlap between them, and only 5 genes commonly methylated in all cell types. Gene expression differences among the cell types mirrored the DNA methylation differences in magnitude, again with little overlap in specific genes affected. Gene Ontology analysis of the affected genes identified common cellular process affected in all three cell types without the same genes contributing. These data suggest that most DNA methylation differences are driven by the demands imposed by each cell type with schizophrenia-associated differences also being cell-type specific. Thus DNA methylation may not be a cause of schizophrenia-associated differences in cell functions in these cells but rather a downstream consequence of some unidentified causative mechanisms. This dataset represents the DNA methylation part of the study. The gene expression data is deposited under accession E-MTAB-5016.

Project description:Epigenetic modification of the mammalian genome by DNA methylation (5-methylcytosine) has a profound impact on chromatin structure, gene expression and maintenance of cellular identity. Recent demonstration that members of the Ten-eleven translocation (Tet) family proteins can convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) raised the possibility that Tet proteins are capable of establishing a distinct epigenetic state. We have recently demonstrated that Tet1 is specifically expressed in murine embryonic stem (ES) cells and is required for ES cell self-renewal and maintenance. Using chromatin immunoprecipitation coupled with high-throughput DNA sequencing (ChIP-seq), here we show that Tet1 is preferentially bound to CpG-rich sequences at promoters of both transcriptionally active and Polycomb-repressed genes. Despite a general increase in levels of DNA methylation at Tet1 binding-sites, Tet1 depletion does not lead to down-regulation of all the Tet1 targets. Interestingly, while Tet1-mediated promoter hypomethylation is required for maintaining the expression of a group of transcriptionally active genes, it is also required for repression of Polycomb-targeted developmental regulators. Tet1 contributes to silencing of this group of genes by facilitating recruitment of PRC2 to CpG-rich gene promoters. Thus, our study not only establishes a role for Tet1 in modulating DNA methylation levels at CpG-rich promoters, but also reveals a dual function of Tet1 in promoting transcription of pluripotency factors as well as participating in the repression of Polycomb-targeted developmental regulators. Mouse ES cells infected with control knockdown (KD) or Tet1 KD lentiviruses were FACS-sorted for RNA extraction and hybridization on Affymetrix microarrays. We also investigated the effect of Nanog overexpression (OE) in Tet1 KD mouse ES cells on dys-regulated Tet1 targets. We have collected four biologically independent replicates for each treatment.

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Co-expression network analysis from genes involved with neural-differentiation shows specific pattern in patients with schizophrenia

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