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Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation
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, Molecular Medicine.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine.
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2009 (English)In: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 19, no 1, 1-11 p.Article in journal (Refereed) Published
Abstract [en]

To identify genes that are regulated by cis-acting functional elements in acute lymphoblastic leukemia (ALL) we determined the allele-specific expression (ASE) levels of 2, 529 genes by genotyping a genome-wide panel of single nucleotide polymorphisms in RNA and DNA from bone marrow and blood samples of 197 children with ALL. Using a reproducible, quantitative genotyping method and stringent criteria for scoring ASE, we found that 16% of the analyzed genes display ASE in multiple ALL cell samples. For most of the genes, the level of ASE varied largely between the samples, from 1.4-fold overexpression of one allele to apparent monoallelic expression. For genes exhibiting ASE, 55% displayed bidirectional ASE in which overexpression of either of the two SNP alleles occurred. For bidirectional ASE we also observed overall higher levels of ASE and correlation with the methylation level of these sites. Our results demonstrate that CpG site methylation is one of the factors that regulates gene expression in ALL cells.

Place, publisher, year, edition, pages
2009. Vol. 19, no 1, 1-11 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-98392DOI: 10.1101/gr.083931.108ISI: 000262200000001PubMedID: 18997001OAI: oai:DiVA.org:uu-98392DiVA: diva2:174350
Available from: 2009-02-20 Created: 2009-02-20 Last updated: 2017-12-13Bibliographically 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)
Opponent
Supervisors
Available from: 2009-03-27 Created: 2009-03-06 Last updated: 2009-03-27Bibliographically approved
2. Gene Expression and DNA Methylation in Acute Lymphoblastic Leukemia
Open this publication in new window or tab >>Gene Expression and DNA Methylation in Acute Lymphoblastic Leukemia
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pediatric acute lymphoblastic leukemia (ALL) is the most common malignancy in children, which results from the malignant transformation of progenitor cells in the bone marrow into leukemic cells. The precise mechanisms for this transformation are not well defined, however recent studies suggest that aberrant regulation of gene expression or DNA methylation may play an important role. Hence, the aim of this thesis was to use novel methods to investigate genome-wide gene expression and DNA methylation patterns in a large collection of primary ALL cells from pediatric patients. With these studies, we aimed to increase the understanding of factors that regulate gene expression and DNA methylation in ALL.

In the first study of the thesis we found that data obtained from genome-wide digital gene expression analysis enabled excellent cytogenetic subtype-specific classification of ALL cells and revealed new features of gene expression within the disease, such as prevalent antisense transcription and alternative polyadenylation. In the second study we used technology developed for large-scale single nucleotide polymorphism (SNP) genotyping for quantitative analysis of allele-specific gene expression (ASE), revealing widespread ASE in ALL cells. Analysis of DNA methylation in promoter regions of the genes displaying ASE using DNA-microarrays revealed frequent regulation of gene expression by DNA methylation. In the third study, using the same DNA methylation array, we identified differences in the DNA methylation patterns in ALL cells at diagnosis compared to healthy mononuclear cells from the bone marrow of the same children at remission. In the fourth study we measured the DNA methylation of >450,000 CpG sites across the genome in a large collection of ALL samples and non-leukemic control cells. We found that ALL cells displayed highly divergent DNA methylation patterns depending on their cytogenetic subtype and widespread regions of differential methylation were enriched for repressive histone marks. DNA methylation levels at distinct regions in the genome were substantially increased at relapse compared to matched cells from diagnosis.

Collectively, the results presented in this thesis provide new insights into the patterns of gene expression and epigenetic changes in ALL and further increase our understanding of the development and progression of the disease, which will hopefully lead to better treatment options in the future.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 799
Keyword
Digital gene expression, Allele-specific gene expression, DNA methylation, Epigenetics, Acute lymphoblastic leukemia
National Category
Pediatrics Hematology Cancer and Oncology
Research subject
Molecular Medicine
Identifiers
urn:nbn:se:uu:diva-179680 (URN)978-91-554-8442-2 (ISBN)
Public defence
2012-10-05, Rudbecksalen, Rudbeck Laboratoriet, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2012-09-13 Created: 2012-08-21 Last updated: 2013-01-22Bibliographically approved

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Lundmark, AndersNordlund, JessicaLönnerholm, GudmarSyvänen, Ann-Christine

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