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Allelic imbalance in gene expression as a guide to cis-acting regulatory single nucleotide polymorphisms in cancer cells
KTH, Skolan för bioteknologi (BIO), Genteknologi.
Visa övriga samt affilieringar
2007 (Engelska)Ingår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 35, nr 5, s. E34-Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Using the relative expression levels of two SNIP 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 Al as an initial approach. We selected 160 expressed candidate genes that are involved in cancer and anticancer drug resistance for analysis of All 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 Al 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 SNIP 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.

Ort, förlag, år, upplaga, sidor
2007. Vol. 35, nr 5, s. E34-
Nationell ämneskategori
Biokemi och molekylärbiologi
Identifikatorer
URN: urn:nbn:se:kth:diva-7865DOI: 10.1093/nar/gkl1152ISI: 000246371200037Scopus ID: 2-s2.0-34247133388OAI: oai:DiVA.org:kth-7865DiVA, id: diva2:13016
Anmärkning
QC 20100621Tillgänglig från: 2007-12-19 Skapad: 2007-12-19 Senast uppdaterad: 2017-12-14Bibliografiskt granskad
Ingår i avhandling
1. Computational and experimental approaches to regulatory genetic variation
Öppna denna publikation i ny flik eller fönster >>Computational and experimental approaches to regulatory genetic variation
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Genetic variation is a strong risk factor for many human diseases, including diabetes, cancer, cardiovascular disease, depression, autoimmunity and asthma. Most of the disease genes identified so far alter the amino acid sequences of encoded proteins. However, a significant number of genetic variants affecting complex diseases may alter the regulation of gene transcription. The map of the regulatory elements in the human genome is still to a large extent unknown, and it remains a challenge to separate the functional regulatory genetic variations from linked neutral variations.

The objective of this thesis was to develop methods for the identification of genetic variation with a potential to affect the transcriptional regulation of human genes, and to analyze potential regulatory polymorphisms in the CD36 glycoprotein, a candidate gene for cardiovascular disease.

An in silico tool for the prediction of regulatory polymorphisms in human genes was implemented and is available at www.cisreg.ca/RAVEN. The tool was evaluated using experimentally verified regulatory single nucleotide polymorphisms (SNPs) collected from the scientific literature, and tested in combination with experimental detection of allele specific expression of target genes (allelic imbalance). Regulatory SNPs were shown to be located in evolutionary conserved regions more often than background SNPs, but predicted transcription factor binding sites were unable to enrich for regulatory SNPs unless additional information linking transcription factors with the target genes were available.

The in silico tool was applied to the CD36 glycoprotein, a candidate gene for cardiovascular disease. Potential regulatory SNPs in the alternative promoters of this gene were identified and evaluated in vitro and in vivo using a clinical study for coronary artery disease. We observed association to the plasma concentrations of inflammation markers (serum amyloid A protein and C-reactive protein) in myocardial infarction patients, which highlights the need for further analyses of potential regulatory polymorphisms in this gene.

Taken together, this thesis describes an in silico approach to identify putative regulatory polymorphisms which can be useful for directing limited laboratory resources to the polymorphisms most likely to have a phenotypic effect.

Ort, förlag, år, upplaga, sidor
Stockholm: Bioteknologi, 2007
Serie
Trita-BIO-Report, ISSN 1654-2312 ; 2007:12
Nyckelord
Molecular biology, Genetics, single nucleotide polymprhism (SNP), regulatory SNP, transcription factor binding site, phylogenetic footprinting, allelic imbalance, EMSA, CD36, cardiovascular disease.
Nationell ämneskategori
Annan industriell bioteknik
Identifikatorer
urn:nbn:se:kth:diva-4593 (URN)978-91-7178-827-6 (ISBN)
Disputation
2008-01-18, FD5, AlbaNova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00
Opponent
Handledare
Tillgänglig från: 2007-12-19 Skapad: 2007-12-19 Senast uppdaterad: 2012-03-20Bibliografiskt granskad

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