Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Expression data SK-N-SH cells treated with risperidone

ABSTRACT: We performed a pharmacotranscriptomic analysis of a human neuroblastoma cell line (SK-N-SH) exposed to risperidone to identify molecular mechanisms involved in the cellular response to risperidone and thus identify candidate genes for pharmacogenetic studies. This study is a part of a convergent functional genomic approach that plans to integrate the data presented here with: data from gene expression analysis of experimental animal brain under treatment with risperidone; and data from gene expression analysis of peripheral blood from first psychotic patients treated with risperidone. Gene expression was assessed by microarray (Human Genome U219 Array) in cells treated with risperidone 10 ÂµM at 6, 24 and 48 h

ORGANISM(S): Homo sapiens

SUBMITTER: Sergi Mas Herrero

PROVIDER: E-GEOD-36678 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics, we observed that compound constitutive activation of M-NM-2-catenin and deletion of Irf8 results in progression of CML-like disease into fatal blast crisis, elevated leukemic potential of BCR-ABL-induced LICs, and accumulation of Imatinib-resistant LICs in GMP-like populations. We found that progression of the disease is tightly connected to the magnitude of gene expression and that activated M-NM-2-catenin enhances a pre-existing Irf8-deficient gene signature that was defined as a M-bM-^@M-^\progression specific signatureM-bM-^@M-^] (PSS). We identified M-NM-2-catenin as an amplifier of disease progression and as a critical step in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for M-NM-2-catenin-driven leukemia and imply both factors as targets in combinatorial therapy. We used microarrays to identify the gene expression signature in GMPs underlying CML-like disease progression and identified distinct classes of up- and down-regulated genes during this process defined as a M-bM-^@M-^\progression specific signature (PSS)M-bM-^@M-^]. GMP populations were sorted from three to four independent pools of control MxCreM-bM-^@M-^SCtnnb1(Ex3)fl/+, Ctnnb1(Ex3)M-bM-^HM-^F/+, Irf8M-bM-^@M-^S/M-bM-^@M-^SCtnnb1(Ex3)fl/+ and Irf8M-bM-^@M-^S/M-bM-^@M-^SCtnnb1(Ex3)M-bM-^HM-^F/+ mice for RNA extraction and hybridization on Affymetrix Mouse 430_2 chip arrays (MG-430 PM peg arrays; Affymetrix GeneChip). Cells were sorted using FACSAria (BD Biosciences Immunocytometry Systems, San Jose, CA) flow cytometers and GMPs defined as lineage depleted LinM-bM-^@M-^S Sca-1M-bM-^@M-^Sc-Kit+CD34+FcR II/IIIhi population. All mice were treated with 400M-BM-5g polyinosinic-polycytidylic acid (poly(I:C)) (Amersham) on day 0, 3 and 5 to induce M-NM-2-catenin activation (MxCre-dependent excision of Exon3 in the M-NM-2-catenin gene). Harvesting of bone marrow cells were performed 10-14 days after the last poly(I:C) injection. We used heterozygous inducible MxCre+Ctnnb1(Ex3)fl/+ mice because of the dominant effect from a single activated Ctnnb1 allele. To validate excision efficiency, genomic DNA from harvested cells was subjected to PCR, as previously described (Huelsken et al., 2001; Scheller et al., 2006).

Project description:Background: Adenosine deaminases that act on RNA (ADARs) bind to double-stranded and structured RNAs and deaminate adenosines to inosines. This A to I editing is widespread and required for normal life and development. Besides mRNAs and repetitive elements, ADARs can target miRNA precursors. Editing of miRNA precursors can affect processing efficiency and alter target specificity. Interestingly, ADARs can also influence miRNA abundance independent of RNA-editing. In mouse embryos where editing levels are low, ADAR2 was found to be the major ADAR protein that affects miRNA abundance. Here we extend our analysis to adult mouse brains where high editing levels are observed. Results: Using Illumina deep sequencing we compare the abundances of mature miRNAs and editing events within them, between wild-type and ADAR2 knockout mice in the adult mouse brain. Reproducible changes in abundance of specific miRNAs are observed in ADAR2 deficient mice. Most of these quantitative changes seem unrelated to A to I editing events. However, many A to G transitions in cDNAs prepared from mature miRNA sequences, reflecting A to I editing events in the RNA, are observed with frequencies reaching up to 80%. About half of these editing events are primarily caused by ADAR2 while a few miRNAs show increased editing in the absence of ADAR2, suggesting preferential editing by ADAR1. Moreover, novel, previously unknown editing events were identified in several miRNAs. In general 64% of all editing events are located within the seed region of mature miRNAs. In one of these cases retargeting of the edited miRNA could be verified in reporter assays. Also, altered processing efficiency upon editing near a processing site could be experimentally verified. Conclusions: ADAR2 can significantly influence the abundance of certain miRNAs in the brain. Only in a few cases changes in miRNA abundance can be explained by miRNA editing. Thus, ADAR2 binding to miRNA precursors, without editing them, may influence their processing and thereby abundance. ADAR1 and ADAR2 have both overlapping and distinct specificities for editing of miRNA editing sites. Over 60% of editing occurs in the seed region possibly changing target specificities for many edited miRNAs. Examination of the effect of ADAR2 on gene expression in mature mouse wildtype and ADAR2 knockout brain using AffymetrixM-BM-. GeneChipM-BM-. Whole Transcript (WT) Expression Arrays (Analysis by KFB Regensburg, Germany)

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Expression data SK-N-SH cells treated with risperidone

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