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Chromosome-wide gene regulatory mechanisms in Drosophila melanogaster
Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology). (Jan Larsson)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In Drosophila there are two different chromosome-wide targeting systems, the dosage compensation system that equalizes the transcriptional output from X-linked genes between males and females, and the regulation of the 4th chromosome mediated by the POF protein.

 

The best studied of these two mechanisms is the dosage compensation system. To attain dosage compensation in Drosophila at least five different proteins, encoded by the male-specific lethal genes msl1, msl2, msl3, mle and mof, are required. These proteins together with two non-coding RNAs (roX1 and roX2) form a dosage compensation complex (MSL complex), which binds exclusively to the X chromosome in Drosophila males and up-regulates the transcription approximately two times.

 

In this thesis I show that roX1 and roX2 are most likely the only non-coding RNAs within the MSL complex. As expected, the roX transcripts were enriched within the MSL complex. Interestingly, one additional transcript was identified within the MSL complex. This transcript did not associate with the X chromosome and is therefore not believed to be involved in up-regulation of the X-linked genes. This transcript encodes for the rate limiting component in the MSL complex, the MSL2 protein. A model is proposed in which free, partial or complete, MSL complex feed-back regulates the amount of msl2 transcript, and thereby limits the MSL complex production.

 

The second chromosome-wide regulatory system in flies acts on an autosome, the heterochromatic 4th chromosome. This regulation is a balancing mechanism between at least two different proteins, the chromosome 4 specific protein painting of fourth (POF) and heterochromatin protein 1 (HP1). POF binds to nascent RNAs transcribed from the 4th chromosome and HP1 target the same set of genes at the chromatin level. POF stimulates the transcribed genes, while HP1 represses them; together they create the most optimal condition for these genes. This type of balancing mechanism may be a more general way to fine-tune transcription at a chromosome-wide level and raises the question about autosomal gene regulation as a general mechanism.

Place, publisher, year, edition, pages
Umeå: Arkitektkopia , 2010. , 75 p.
Keyword [en]
Chromatin structure, Drosophila, POF, disage compensation, gene expression, MSL, heterochromatin
National Category
Genetics
Research subject
Genetics
Identifiers
URN: urn:nbn:se:umu:diva-33928ISBN: 978-91-7459-017-3 (print)OAI: oai:DiVA.org:umu-33928DiVA: diva2:318770
Public defence
2010-06-04, Major Groove, byggnad 6L, Umeå Universitet, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2010-05-12 Created: 2010-05-10 Last updated: 2011-05-17Bibliographically approved
List of papers
1. Painting of fourth and chromosome-wide regulation of the 4th chromosome in Drosophila melanogaster.
Open this publication in new window or tab >>Painting of fourth and chromosome-wide regulation of the 4th chromosome in Drosophila melanogaster.
2007 (English)In: EMBO J, ISSN 0261-4189, Vol. 26, no 9, 2307-2316 p.Article in journal (Refereed) Published
Abstract [en]

Drosophila melanogaster exhibits two expression-regulating systems that target whole, specific chromosomes: the dosage compensation system whereby the male-specific lethal complex doubles transcription of genes on the male X-chromosome and the chromosome 4-specific protein Painting of fourth, POF. POF is the first example of an autosome-specific protein and its presence raises the question of the universality of chromosome-specific regulation. Here we show that POF and heterochromatin protein 1 (HP1) are involved in the global regulation of the 4th chromosome. Contrary to previous conclusions, Pof is not essential for survival of diplo-4th karyotype flies. However, Pof is essential for survival of haplo-4th individuals and expression of chromosome 4 genes in diplo-4th individuals is decreased in the absence of Pof. Mapping of POF using chromatin immunoprecipitation suggested that it binds within genes. Furthermore, we show that POF binding is dependent on heterochromatin and that POF and HP1 bind interdependently to the 4th chromosome. We propose a balancing mechanism involving POF and HP1 that provides a feedback system for fine-tuning expression status of genes on the 4th chromosome.

Keyword
Animals, Chromosomal Proteins; Non-Histone/genetics/*metabolism, Chromosomes/*genetics, Dosage Compensation; Genetic, Drosophila Proteins/genetics/*metabolism, Drosophila melanogaster/genetics/*physiology, Gene Expression Regulation, Heterochromatin/*physiology, Male
Identifiers
urn:nbn:se:umu:diva-17029 (URN)17318176 (PubMedID)
Available from: 2008-01-12 Created: 2008-01-12 Last updated: 2012-04-11Bibliographically approved
2. POF and HP1 bind expressed exons, suggesting a balancing mechanism for gene regulation
Open this publication in new window or tab >>POF and HP1 bind expressed exons, suggesting a balancing mechanism for gene regulation
2007 (English)In: PLoS Genet, ISSN 1553-7404, Vol. 3, no 11, e209- p.Article in journal (Refereed) Published
Abstract [en]

Two specific chromosome-targeting and gene regulatory systems are present in Drosophila melanogaster. The male X chromosome is targeted by the male-specific lethal complex believed to mediate the 2-fold up-regulation of the X-linked genes, and the highly heterochromatic fourth chromosome is specifically targeted by the Painting of Fourth (POF) protein, which, together with heterochromatin protein 1 (HP1), modulates the expression level of genes on the fourth chromosome. Here we use chromatin immunoprecipitation and tiling microarray analysis to map POF and HP1 on the fourth chromosome in S2 cells and salivary glands at high resolution. The enrichment profiles were complemented by transcript profiles to examine the link between binding and transcripts. The results show that POF specifically binds to genes, with a strong preference for exons, and the HP1 binding profile is a mirror image of POF, although HP1 displays an additional "peak" in the promoter regions of bound genes. HP1 binding within genes is much higher than the basal HP1 enrichment on Chromosome 4. Our results suggest a balancing mechanism for the regulation of the fourth chromosome where POF and HP1 competitively bind at increasing levels with increased transcriptional activity. In addition, our results contradict transposable elements as a major nucleation site for HP1 on the fourth chromosome.

Identifiers
urn:nbn:se:umu:diva-17872 (URN)10.1371/journal.pgen.0030209 (DOI)18020713 (PubMedID)
Available from: 2008-01-12 Created: 2008-01-12 Last updated: 2010-05-12Bibliographically approved
3. POF Regulates the Expression of Genes on the Fourth Chromosome in Drosophila melanogaster by Binding to Nascent RNA
Open this publication in new window or tab >>POF Regulates the Expression of Genes on the Fourth Chromosome in Drosophila melanogaster by Binding to Nascent RNA
2012 (English)In: Molecular and Cellular Biology, ISSN 0270-7306, E-ISSN 1098-5549, Vol. 32, no 11, 2121-2134 p.Article in journal (Other academic) Published
Abstract [en]

In Drosophila, two chromosome-wide compensatory systems have been characterized: the dosage compensation system that acts on the male X chromosome and the chromosome-specific regulation of genes located on the heterochromatic fourth chromosome. Dosage compensation in Drosophila is accomplished by hypertranscription of the single male X chromosome mediated by the male-specific lethal (MSL) complex. The mechanism of this compensation is suggested to involve enhanced transcriptional elongation mediated by the MSL complex, while the mechanism of compensation mediated by the painting of fourth (POF) protein on the fourth chromosome has remained elusive. Here, we show that POF binds to nascent RNA, and this binding is associated with increased transcription output from chromosome 4. We also show that genes located in heterochromatic regions spend less time in transition from the site of transcription to the nuclear envelope. These results provide useful insights into the means by which genes in heterochromatic regions can overcome the repressive influence of their hostile environment.

Place, publisher, year, edition, pages
American Society for Microbiology, 2012
National Category
Genetics Biochemistry and Molecular Biology
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-33925 (URN)10.1128/MCB.06622-11 (DOI)000304293000007 ()22473994 (PubMedID)
External cooperation:
Note

First published in thesis in manuscript form with title: "POF regulates the 4th chromosome through association to nascent RNA"

Available from: 2010-05-10 Created: 2010-05-10 Last updated: 2017-12-12Bibliographically approved
4. msl2 mRNA is bound by free nuclear MSL complex in Drosophila melanogaster
Open this publication in new window or tab >>msl2 mRNA is bound by free nuclear MSL complex in Drosophila melanogaster
2011 (English)In: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 39, no 15, 6428-6439 p.Article in journal (Refereed) Published
Abstract [en]

In Drosophila, the global increase in transcription from the male X chromosome to compensate for its monosomy is mediated by the male-specific lethal (MSL) complex consisting of five proteins and two non-coding RNAs, roX1 and roX2. After an initial sequence-dependent recognition by the MSL complex of 150-300 high affinity sites, the spread to the majority of the X-linked genes depends on local MSL-complex concentration and active transcription. We have explored whether any additional RNA species are associated with the MSL complex. No additional roX RNA species were found, but a strong association was found between a spliced and poly-adenylated msl2 RNA and the MSL complex. Based on our results, we propose a model in which a non-chromatin-associated partial or complete MSL-complex titrates newly transcribed msl2 mRNA and thus regulates the amount of available MSL complex by feedback. This represents a novel mechanism in chromatin structure regulation.

Place, publisher, year, edition, pages
Oxford Journals, 2011
National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-43980 (URN)10.1093/nar/gkr236 (DOI)21551218 (PubMedID)
Funder
Swedish Research Council
Available from: 2011-05-17 Created: 2011-05-17 Last updated: 2017-12-11

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Johansson, Anna-Mia

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