Extreme clonality in lymphoblastoid cell lines with implications for allele specific expression analyses.
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ABSTRACT:
SUBMITTER: Plagnol V
PROVIDER: S-EPMC2494943 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Women and men have different risks for certain diseases and they often respond differently to treatment. These differences could be due to the sex-specific differences in the expression of genes related to primary disease susceptibility or pharmacodynamic targets. To evaluate the sex-specific pattern of gene expression, we compared gene expression levels using a publicly available microarray dataset of 233 (115 women and 118 men) lymphoblastoid cell lines. From the 4799 probes meeting a specified minimal level of expression, 10 genes (P<0.005, permutation adjusted false discovery rate less than 50%) located on autosomal chromosomes were identified using a permutation-based approach. These genes were found to be over-represented in certain gene ontology terms of biological process (cell adhesion, apoptosis, transcription and signal transduction), and molecular function (structural molecule activity, zinc ion binding, transcription factor activity and protein binding). A Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that two known pathways are over-represented: adherens junction and cytokine-cytokine receptor interaction.
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Project description:Allele-specific gene expression, ASE, is an important aspect of gene regulation. We developed a novel method MBASED, meta-analysis based allele-specific expression detection for ASE detection using RNA-seq data that aggregates information across multiple single nucleotide variation loci to obtain a gene-level measure of ASE, even when prior phasing information is unavailable. MBASED is capable of one-sample and two-sample analyses and performs well in simulations. We applied MBASED to a panel of cancer cell lines and paired tumor-normal tissue samples, and observed extensive ASE in cancer, but not normal, samples, mainly driven by genomic copy number alterations.
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Project description:Cis-regulatory variants are predicted to mediate the majority of the common genetic risk associated to complex disease, yet the specific causal variants have thus far been poorly characterized. Allele-specific (AS) assessment of chromatin modifications has the potential to elucidate specific cis-regulatory mechanisms. However, development of chromatin landscapes at allelic resolution has been challenging since sites of variable signal strength require substantial read depth not commonly applied in next-generation sequencing based approaches. In this study, we addressed this by directly assessing AS chromatin states through parallel analyses of input DNA and chromatin immunoprecipitates (ChIP) on high-density Illumina genotyping arrays. Allele-specificity for the histone modifications H3K4me1, H3K4me3, H3K27ac, H3K27me3 and H3K36me3 was assessed using ChIP samples generated from 14 lymphoblast and 6 fibroblast cell lines.
2013-10-18 | GSE51272 | GEO
Project description:Allelic variation in gene expression is common in human genome. To understand genetic and epigenetic basis of allelic gene expression variation, we conducted allele specific RNA polymerase occupancy and allele specific gene expression analysis in CEPH lymphoblastoid cell lines.
2014-12-31 | GSE35099 | GEO
Project description:Epstein-Barr virus (EBV) can infect human B cells and is associated with various types of B cell lymphomas. Studies on the global alterations of the cellular pathways mediated by EBV-induced B cell transformation are limited. In the present study, microarray analysis was performed following generation of two EBV-infected B-lymphoblastoid cell lines (BLCL), in which normal B cells obtained from two healthy Thai individuals and transcriptomic profiles were compared with their respective normal B cells. The two EBV-transformed BLCL datasets exhibited a high degree of similarity between their RNA expression profiles, whereas the two normal B-cell datasets did not exhibit the same degree of similarity in their RNA expression profiles. Differential gene expression analysis was performed, and the results showed that EBV infection was able to dysregulate several cellular pathways in the human B-cell genes involved in cancer and cell activation, such as the MAPK, WNT and PI3K-Akt signaling pathways, which were upregulated in the BLCL and were associated with increased cellular proliferation and immortalization of EBV-infected B cells. Expression of proteins located in the plasma membrane, which initiate a biological response to ligand binding, were also notably upregulated. Expression of genes involved in cell cycle control, the p53 signaling pathway and cellular senescence were downregulated. In conclusion, genes that were markedly upregulated by EBV included those involved in the acquisition of a tumorigenic phenotype of BLCL, which was positively correlated with several hallmarks of cancer.
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Project description:BackgroundReadily accessible samples such as peripheral blood or cell lines are increasingly being used in large cohorts to characterise gene expression differences between a patient group and healthy controls. However, cell and RNA isolation procedures and the variety of cell types that make up whole blood can affect gene expression measurements. We therefore systematically investigated global gene expression profiles in peripheral blood from six individuals collected during two visits by comparing five of the following cell and RNA isolation methods: whole blood (PAXgene), peripheral blood mononuclear cells (PBMCs), lymphoblastoid cell lines (LCLs), CD19 and CD20 specific B-cell subsets.ResultsGene expression measurements were clearly discriminated by isolation method although the reproducibility was high for all methods (range rho = 0.90-1.00). The PAXgene samples showed a decrease in the number of expressed genes (P < 1*10(-16)) with higher variability (P < 1*10(-16)) compared to the other methods. Differentially expressed probes between PAXgene and PBMCs were correlated with the number of monocytes, lymphocytes, neutrophils or erythrocytes. The correlations (rho = 0.83; rho = 0.79) of the expression levels of detected probes between LCLs and B-cell subsets were much lower compared to the two B-cell isolation methods (rho = 0.98). Gene ontology analysis of detected genes showed that genes involved in inflammatory responses are enriched in B-cells CD19 and CD20 whereas genes involved in alcohol metabolic process and the cell cycle were enriched in LCLs.ConclusionGene expression profiles in blood-based samples are strongly dependent on the predominant constituent cell type(s) and RNA isolation method. It is crucial to understand the differences and variability of gene expression measurements between cell and RNA isolation procedures, and their relevance to disease processes, before application in large clinical studies.
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Project description:BackgroundStatins are widely prescribed to lower plasma low-density lipoprotein cholesterol levels. Though statins reduce cardiovascular disease risk overall, statin efficacy varies, and some people experience adverse side effects while on statin treatment. Statins also have pleiotropic effects not directly related to their cholesterol-lowering properties, but the mechanisms are not well understood. To identify potential genetic modulators of clinical statin response, we looked for genetic variants associated with statin-induced changes in gene expression (differential eQTLs or deQTLs) in lymphoblastoid cell lines (LCLs) derived from participants of the Cholesterol and Pharmacogenetics (CAP) 40 mg/day 6-week simvastatin clinical trial. We exposed CAP LCLs to 2 μM simvastatin or control buffer for 24 h and performed polyA-selected, strand-specific RNA-seq. Statin-induced changes in gene expression from 259 European ancestry or 153 African American ancestry LCLs were adjusted for potential confounders prior to association with genotyped and imputed genetic variants within 1 Mb of each gene's transcription start site.ResultsFrom the deQTL meta-analysis of the two ancestral populations, we identified significant cis-deQTLs for 15 genes (TBC1D4, MDGA1, CHI3L2, OAS1, GATM, ASNSD1, GLUL, TDRD12, PPIP5K2, OAS3, SERPINB1, ANKDD1A, DTD1, CYFIP2, and GSDME), eight of which were significant in at least one of the ancestry subsets alone. We also conducted eQTL analyses of the endogenous (control-treated), statin-treated, and average of endogenous and statin-treated LCL gene expression levels. We identified eQTLs for approximately 6000 genes in each of the three (endogenous, statin-treated, and average) eQTL meta-analyses, with smaller numbers identified in the ancestral subsets alone.ConclusionsSeveral of the genes in which we identified deQTLs have functions in human health and disease, such as defense from viruses, glucose regulation, and response to chemotherapy drugs. This suggests that DNA variation may play a role in statin effects on various health outcomes. These findings could prove useful to future studies aiming to assess benefit versus risk of statin treatment using individual genetic profiles.
| S-EPMC7430882 | biostudies-literature
Project description:Cis-regulatory variants are predicted to mediate the majority of the common genetic risk associated to complex disease, yet the specific causal variants have thus far been poorly characterized. Allele-specific (AS) assessment of chromatin modifications has the potential to elucidate specific cis-regulatory mechanisms. However, development of chromatin landscapes at allelic resolution has been challenging since sites of variable signal strength require substantial read depth not commonly applied in next-generation sequencing based approaches. In this study, we addressed this by directly assessing AS chromatin states through parallel analyses of input DNA and chromatin immunoprecipitates (ChIP) on high-density Illumina genotyping arrays. Allele-specificity for the histone modifications H3K4me1, H3K4me3, H3K27ac, H3K27me3 and H3K36me3 was assessed using ChIP samples generated from 14 lymphoblast and 6 fibroblast cell lines. Allele-specificity of chromatin was assessed in 14 lymphoblast and 6 fibroblast cell lines by assaying PolII & histone ChIP samples (H3K4me1, H3K4me3, H3K27ac, H3K27me3, H3K36me3) in parallel with gDNA and cDNA on high-density Illumina genotyping arrays.
2013-10-18 | E-GEOD-51272 | biostudies-arrayexpress
Project description:BACKGROUND:Human Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) have been thought to be a useful model system for pharmacogenomics studies. The purpose of this study was to determine the effect of Epstein-Barr virus transformation on gene expression changes by dexamethasone (Dex) in LCLs and primary B cells (PBCs) derived from the same individuals. PATIENTS AND METHODS:We prepared LCLs and purified PBCs from the same six male donors participating in the Childhood Asthma Management Program clinical trial, and compared mRNA profiles after 6?h incubation with Dex (10?mol/l) or sham buffer. We assessed differential expression and put the list of differentially expressed genes into the web interface of ConsensusPathDB to find the pathway-level interpretation of our genes specified. As a supplementary analysis, we looked at the expression of the Dex-regulated (inducing or repressing) genes in treatment-naive PBCs and LCLs (pre-Dex treatment) from the GSE30916 dataset. RESULTS:By hierarchical clustering, we found clustering of probes by cell types but not by individuals irrespective of Dex treatment. We observed that the Dex-regulated genes significantly overlapped in PBCs and LCLs. In addition, the expression of these genes showed significant correlations between treatment-naive PBCs and LCLs. Common genes showing significantly decreased expressions by the Dex treatment in both cells were enriched in immune responses and proinflammatory signaling pathways. CONCLUSION:Taken together, these results suggest the uses of LCLs are representative of the primary biologic effects of corticosteroids treatment.
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Project description:AimFolate is vital for cell growth and development through its important role in one-carbon metabolism - an essential process in the synthesis of amino acids and nucleic acids. Folate pathway genes have been considered as therapeutic targets of drugs for the treatment of cancer and other diseases. Racial and ethnic disparities of folate metabolism and outcome of antifolate therapies have been reported. In this study, we evaluate the genetic regulation for expression and alternative splicing of folate related genes in HapMap lymphoblastoid cell lines (LCLs) of individuals of European and African descent.Materials & methodsGene and exon level expression and alternative splicing of folate pathway genes were compared in LCLs derived from the Centre d'Etude du Polymorphisme Humain (CEPH) from Utah (CEU) and the Yoruba from Ibadan (YRI) using a permutation-based test. A genome-wide association study was performed to search for SNPs associated with folate pathway gene expressions and alternative splicing in the combined population samples.ResultsA total of 52 folate pathway genes were evaluated in the analysis of which 46 were expressed in the LCLs. There were 12 genes (26%) with differential gene-level expression and 23 genes (50%) with differential alternative splicing for exons or UTRs between the CEU and the YRI (permutation p <or= 0.05). The expression level of FPGS and the splicing indices of eight genes (ATP13A2, ASCC3L1, IFIH1, SMARCA5, SMARCA2, SETX, DDX52 and RUVBL2) were found to be associated with SNP genotypes in the combined populations (p < 3.2 x 10(-8), Bonferroni corrected p < 0.05).ConclusionOur study suggests that LCLs are an in vitro system suitable to evaluate the expression levels of folate pathway genes. The differential transcript-level expressions and the differentially alternative splicing events of exons or UTRs and associated SNP markers in 2 populations will enhance our understanding of the folate pathway and, thus, facilitate research in the areas of nutrition and folate metabolism.
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