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Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
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2007 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 35, no 5, e34- p.Article in journal (Refereed) Published
Abstract [en]

Using the relative expression levels of two SNP alleles of a gene in the same sample is an effective approach for identifying cis-acting regulatory SNPs (rSNPs). In the current study, we established a process for systematic screening for cis-acting rSNPs using experimental detection of AI as an initial approach. We selected 160 expressed candidate genes that are involved in cancer and anticancer drug resistance for analysis of AI in a panel of cell lines that represent different types of cancers and have been well characterized for their response patterns against anticancer drugs. Of these genes, 60 contained heterozygous SNPs in their coding regions, and 41 of the genes displayed imbalanced expression of the two cSNP alleles. Genes that displayed AI were subjected to bioinformatics-assisted identification of rSNPs that alter the strength of transcription factor binding. rSNPs in 15 genes were subjected to electrophoretic mobility shift assay, and in eight of these genes (APC, BCL2, CCND2, MLH1, PARP1, SLIT2, YES1, XRCC1) we identified differential protein binding from a nuclear extract between the SNP alleles. The screening process allowed us to zoom in from 160 candidate genes to eight genes that may contain functional rSNPs in their promoter regions.

Place, publisher, year, edition, pages
2007. Vol. 35, no 5, e34- p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-24501DOI: 10.1093/nar/gkl1152ISI: 000246371200037PubMedID: 17267408OAI: oai:DiVA.org:uu-24501DiVA: diva2:52275
Available from: 2007-02-08 Created: 2007-02-08 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Gene Expression in Cancer Cells: Detection of Splice Variants, Allele-specific Expression and DNA Methylation
Open this publication in new window or tab >>Gene Expression in Cancer Cells: Detection of Splice Variants, Allele-specific Expression and DNA Methylation
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The human genome sequencing project has provided a wealth of information on sequence variation between individuals. The surprisingly low number of genes in the human genome is compensated for by a complex regulation of gene expression. New methods are now being developed for the discovery and analysis of the regulatory regions of the genome to elucidate factors that affect both normal and disease-associated human genetic variation. In parallel with identification of DNA sequence variation, efforts are being made to unravel the next layer of information - epigenetic modifications of the genome. The studies in this thesis describe the application of methods for genotyping single nucleotide polymorphisms (SNPs) in DNA for the analysis of gene transcripts in cancer cells. We performed quantitative analysis of splice variants and screened for allele-specific gene expression (ASE) in cancer cells using the tag-microarray based minisequencing system. This analysis revealed transcript isoforms that were differentially spliced in leukemia cell lines and normal endothelial cell lines. We detected wide-spread allele-specific gene expression in cancer cells that were sensitive or resistant to anti-cancer drugs. In regulatory regions of the genes with ASE we identified putative regulatory SNPs. Using technology developed for large-scale SNP genotyping, we screened for ASE in an internationally unique collection of childhood acute lymphoblastic leukemia (ALL) samples. Analysis of DNA methylation in promoter regions of genes displaying ASE revealed genes, whose expression is regulated by allele-specific DNA methylation. For a subset of these genes we found a correlation between DNA methylation levels and probability of disease-free survival in ALL patients with different chromosomal aberrations. The methylation patterns that we identified constitute excellent candidate markers for subtyping of ALL patients and for stratification of ALL patients based on their probability of disease-free survival and response to drug treatment. The results of this study have increased our understanding of epigenetic changes in ALL cells and will hopefully help to design better treatment plans for the patients to avoid over-treatment and unnecessary side effects.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 433
Identifiers
urn:nbn:se:uu:diva-99067 (URN)978-91-554-7449-2 (ISBN)
Public defence
2009-04-17, Rudbecksalen, Rudbeck Laboratoriet, Uppsala, 13:00 (English)
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Available from: 2009-03-27 Created: 2009-03-06 Last updated: 2009-03-27Bibliographically approved

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Fryknäs, MårtenIsaksson, AndersLarsson, RolfSyvänen, Ann Christine

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