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HP1a, Su(var)3-9, SETDB1 and POF stimulate or repress gene expression depending on genomic position, gene length and expression pattern in Drosophila melanogaster
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jan Larsson)
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Per Stenberg, Computational Life Science Cluster (CLiC))
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jan Larsson)
2013 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 41, no 8, 4481-4494 p.Article in journal (Refereed) Published
Abstract [en]

Heterochromatin protein 1a (HP1a) is a chromatin-associated protein important for the formation and maintenance of heterochromatin. In Drosophila, the two histone methyltransferases SETDB1 and Su(var)3-9 mediate H3K9 methylation marks that initiates the establishment and spreading of HP1a-enriched chromatin. Although HP1a is generally regarded as a factor that represses gene transcription, several reports have linked HP1a binding to active genes, and in some cases, it has been shown to stimulate transcriptional activity. To clarify the function of HP1a in transcription regulation and its association with Su(var)3-9, SETDB1 and the chromosome 4-specific protein POF, we conducted genome-wide expression studies and combined the results with available binding data in Drosophila melanogaster. The results suggest that HP1a, SETDB1 and Su(var)3-9 repress genes on chromosome 4, where non-ubiquitously expressed genes are preferentially targeted, and stimulate genes in pericentromeric regions. Further, we showed that on chromosome 4, Su(var)3-9, SETDB1 and HP1a target the same genes. In addition, we found that transposons are repressed by HP1a and Su(var)3-9 and that the binding level and expression effects of HP1a are affected by gene length. Our results indicate that genes have adapted to be properly expressed in their local chromatin environment.

Place, publisher, year, edition, pages
2013. Vol. 41, no 8, 4481-4494 p.
Keyword [en]
Drosophila melanogaster, chromatin structure, gene expression, epigenetics
National Category
Genetics
Research subject
Genetics; Molecular Biology
Identifiers
URN: urn:nbn:se:umu:diva-67086DOI: 10.1093/nar/gkt158ISI: 000318569700019PubMedID: 23476027OAI: oai:DiVA.org:umu-67086DiVA: diva2:610626
Available from: 2013-03-18 Created: 2013-03-12 Last updated: 2017-12-06Bibliographically approved
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
Supervisors
Available from: 2013-05-15 Created: 2013-05-13 Last updated: 2013-05-13Bibliographically approved

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Lundberg, Lina EStenberg, PerLarsson, Jan

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