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Buffering of segmental and chromosomal aneuploidies in Drosophila melanogaster
Umeå University, Faculty of Medicine, Molecular Biology. (Stenberg)
Umeå University, Faculty of Medicine, Molecular Biology. (Larsson)
Umeå University, Faculty of Medicine, Molecular Biology. (Jan Larsson)
Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Social Sciences, Department of Statistics. (Computational Life Science Cluster (CLiC))
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2009 (English)In: PLoS genetics, ISSN 1553-7404, Vol. 5, no 5, e1000465- p.Article in journal (Refereed) Published
Abstract [en]

Chromosomal instability, which involves the deletion and duplication of chromosomes or chromosome parts, is a common feature of cancers, and deficiency screens are commonly used to detect genes involved in various biological pathways. However, despite their importance, the effects of deficiencies, duplications, and chromosome losses on the regulation of whole chromosomes and large chromosome domains are largely unknown. Therefore, to explore these effects, we examined expression patterns of genes in several Drosophila deficiency hemizygotes and a duplication hemizygote using microarrays. The results indicate that genes expressed in deficiency hemizygotes are significantly buffered, and that the buffering effect is general rather than being mainly mediated by feedback regulation of individual genes. In addition, differentially expressed genes in haploid condition appear to be generally more strongly buffered than ubiquitously expressed genes in haploid condition, but, among genes present in triploid condition, ubiquitously expressed genes are generally more strongly buffered than differentially expressed genes. Furthermore, we show that the 4th chromosome is compensated in response to dose differences. Our results suggest general mechanisms have evolved that stimulate or repress gene expression of aneuploid regions as appropriate, and on the 4th chromosome of Drosophila this compensation is mediated by Painting of Fourth (POF).

Place, publisher, year, edition, pages
2009. Vol. 5, no 5, e1000465- p.
National Category
Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:umu:diva-22466DOI: 10.1371/journal.pgen.1000465PubMedID: 19412336OAI: oai:DiVA.org:umu-22466DiVA: diva2:216736
Available from: 2009-05-11 Created: 2009-05-11 Last updated: 2013-05-13
In thesis
1. Aneuploidy compensatory mechanisms and genome-wide regulation of gene expression in Drosophila melanogaster
Open this publication in new window or tab >>Aneuploidy compensatory mechanisms and genome-wide regulation of gene expression in Drosophila melanogaster
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Stimulation or repression of gene expression by genome-wide regulatory mechanisms is an important epigenetic regulatory function which can act to efficiently regulate larger regions or specific groups of genes, for example by compensating for loss or gain of chromosome copy numbers. In Drosophila melanogaster there are two known chromosome-wide regulatory systems; the MSL complex, which mediates dosage compensation of the single male X-chromosome and POF, which stimulates expression from the heterochromatic 4th chromosome. POF also interacts with the heterochromatin inducing protein HP1a, which represses expression from the 4th chromosome but which also has been assigned stimulatory functions. In addition to these two, there is another more elusive and less well-characterized genome-wide mechanism called buffering, which can act to balance transcriptional output of aneuploidy regions of the genome (i.e. copy number variation).

In my thesis, I describe the presence of a novel physical link between dosage compensation and heterochromatin; mediate by two female-specific POF binding sites, proximal to roX1 and roX2 on the X chromosome (the two non-coding RNAs in the MSL complex). These sites can also provide clues to the mechanisms behind targeting of chromosome-specific proteins. Furthermore, to clarify the conflicting reports about the function of HP1a, I have suggested a mechanism in which HP1a has adopted its function to different genomic locations and gene types. Different binding mechanisms to the promoter vs. the exon of genes allows HP1a to adopt opposite functions; at the promoter, HP1a binding opens up the chromatin structure and stimulates gene expression, whereas the binding to exons condense the chromatin and thus, represses expression. This also causes long genes to be more bound and repressed by HP1a. Moreover, I show that buffering of monosomic regions is a weak but significant response to loss of chromosomal copy numbers, and that this is mediated via a general mechanism which mainly acts on differentially expressed genes, where the effect becomes stronger for long genes. I also show that POF is the factor which compensates for copy number loss of chromosome 4.

Place, publisher, year, edition, pages
Umeå: Umeå Universitet, 2013. 74 p.
Keyword
Genome-wide gene regulation, aneuploidy, buffering, HP1a, POF, SETDB1, Su(var)3-9, MSL, roX
National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-70302 (URN)978-91-7459-659-5 (ISBN)978-91-7459-660-1 (ISBN)
Public defence
2013-06-05, Byggnad 6E, sal E04, Umeå Universitet, Umeå, 09:00 (English)
Opponent
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Available from: 2013-05-15 Created: 2013-05-13 Last updated: 2013-05-13Bibliographically approved

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Stenberg, PerLundberg, Lina EJohansson, Anna-MiaRydén, PatrikSvensson, Malin JLarsson, Jan
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Molecular BiologyDepartment of Mathematics and Mathematical StatisticsDepartment of StatisticsDepartment of Molecular Biology (Faculty of Science and Technology)
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