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Alternative promoter usage of the membrane glycoprotein CD36
KTH, School of Biotechnology (BIO), Gene Technology.
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2006 (English)In: BMC Molecular Biology, ISSN 1471-2199, Vol. 7, 8- p.Article in journal (Refereed) Published
Abstract [en]

Background: CD36 is a membrane glycoprotein involved in a variety of cellular processes such as lipid transport, immune regulation, hemostasis, adhesion, angiogenesis and atherosclerosis. It is expressed in many tissues and cell types, with a tissue specific expression pattern that is a result of a complex regulation for which the molecular mechanisms are not yet fully understood. There are several alternative mRNA isoforms described for the gene. We have investigated the expression patterns of five alternative first exons of the CD36 gene in several human tissues and cell types, to better understand the molecular details behind its regulation.

Results: We have identified one novel alternative first exon of the CD36 gene, and confirmed the expression of four previously known alternative first exons of the gene. The alternative transcripts are all expressed in more than one human tissue and their expression patterns vary highly in skeletal muscle, heart, liver, adipose tissue, placenta, spinal cord, cerebrum and monocytes. All alternative first exons are upregulated in THP-1 macrophages in response to oxidized low density lipoproteins. The alternative promoters lack TATA-boxes and CpG islands. The upstream region of exon 1b contains several features common for house keeping gene and monocyte specific gene promoters.

Conclusion: Tissue-specific expression patterns of the alternative first exons of CD36 suggest that the alternative first exons of the gene are regulated individually and tissue specifically. At the same time, the fact that all first exons are upregulated in THP-1 macrophages in response to oxidized low density lipoproteins may suggest that the alternative first exons are coregulated in this cell type and environmental condition. The molecular mechanisms regulating CD36 thus appear to be unusually complex, which might reflect the multifunctional role of the gene in different tissues and cellular conditions.

Place, publisher, year, edition, pages
2006. Vol. 7, 8- p.
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-7866DOI: 10.1186/1471-2199-7-8ISI: 000238398300001Scopus ID: 2-s2.0-33744946520OAI: oai:DiVA.org:kth-7866DiVA: diva2:13017
Note
QC 20100621Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2012-03-20Bibliographically approved
In thesis
1. Computational and experimental approaches to regulatory genetic variation
Open this publication in new window or tab >>Computational and experimental approaches to regulatory genetic variation
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
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.

Place, publisher, year, edition, pages
Stockholm: Bioteknologi, 2007
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2007:12
Keyword
Molecular biology, Genetics, single nucleotide polymprhism (SNP), regulatory SNP, transcription factor binding site, phylogenetic footprinting, allelic imbalance, EMSA, CD36, cardiovascular disease.
National Category
Other Industrial Biotechnology
Identifiers
urn:nbn:se:kth:diva-4593 (URN)978-91-7178-827-6 (ISBN)
Public defence
2008-01-18, FD5, AlbaNova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00
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Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2012-03-20Bibliographically approved

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