Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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RNAi knock down of PLC gamma 2, CaMKII, PKC delta and Pyk2 in mouse B cell line A20 after stimulation by anti-IgG to examine the adaptation response of the BCR-dependent intracellular signaling network

ABSTRACT: We examined the adaptation response of the BCR-dependent intracellular signaling network, to targeted perturbations induced through siRNA-mediated depletion of select signaling intermediates. The robustness of this network was found to derive from the fact that its constituent nodes displayed graded sensitivities to these perturbations. Importantly, this latter property also facilitated generation of perturbation-unique calibration of signal at individual nodes, with a corresponding effect on the cellular phenotypic response. Subsequently generated data-driven models revealed that the information specifying cellular phenotypic responses was not coded within variations of groups of nodes acting in a discrete manner. Rather, characteristic signaling features were selectively extracted from the majority of the constituent nodes, and then integrated to define a response-specific axis. Thus, stimulus-induced cell fate decisions are governed through a mechanism that defines the composition of signal extracted, from the overall noise provided by the assortment of signals generated at each of the nodes. The microarray experiment was performed here to identify differences in cellular responses upon various cellular perturbations in terms of gene expression profile. Cells were transfected with specific siRNAs against PLC gamma 2, CaMKII, PKC delta and Pyk2 in addition to mock siRNAs.

ORGANISM(S): Mus musculus

SUBMITTER: Helena Ahlfors

PROVIDER: E-TABM-360 | 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.

Dataset Information

RNAi knock down of PLC gamma 2, CaMKII, PKC delta and Pyk2 in mouse B cell line A20 after stimulation by anti-IgG to examine the adaptation response of the BCR-dependent intracellular signaling network

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