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In vivo analysis of Suppressor of zeste 12´s different isoforms
Umeå University, Faculty of Medicine, Molecular Biology. (Åsa Rasmuson-Lestander)
Umeå University, Faculty of Medicine, Molecular Biology. (Åsa Rasmuson-Lestander)
Umeå University, Faculty of Medicine, Molecular Biology. (Åsa Rasmuson-Lestander)
Umeå University, Faculty of Medicine, Medical Biosciences.
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(English)Manuscript (Other academic)
Abstract [en]

Polycomb Group (PcG) genes are known to encode a large chromatin-associated family of proteins which are involved in genomic regulation of many cellular processes. Su(z)12 is a key component in PcG silencing. It is needed for three levels of methylation of histone 3 lysine 27 in vivo in Drosophila. Here, we report that Su(z)12 may exist in different isoforms and that these isoforms are spatially and temporally regulated. The biological function of the Su(z)12-A and -B isoforms seems to be very different. For instance the transgenic Su(z)12-B and the human homolog SUZ12, but not Su(z)12-A, rescue Su(z)12 mutants. Furthermore, transgenic flies over-expressing Su(z)12-B show typical homeotic transformation phenotypes, while over-expression of Su(z)12-A does not. However, the two isoforms appears to be able to substitute for each other in some aspects. During larval and pupal stages, Su(z)12-A seems to play the main role. 

Keyword [en]
Su(z)12, expression, isoforms, Drosophila
Identifiers
URN: urn:nbn:se:umu:diva-18656OAI: oai:DiVA.org:umu-18656DiVA: diva2:174313
Available from: 2009-02-20 Created: 2009-02-20 Last updated: 2010-01-14Bibliographically approved
In thesis
1. Expression and function of Suppressor of zeste 12 in Drosophila melanogaster
Open this publication in new window or tab >>Expression and function of Suppressor of zeste 12 in Drosophila melanogaster
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The development of animals and plants needs a higher order of regulation of gene expression to maintain proper cell state. The mechanisms that control what, when and where a gene should (or should not) be expressed are essential for correct organism development. The Polycomb group (PcG) is a family of genes responsible for maintaining gene silencing and Suppressor of zeste 12 (Su(z)12) is one of the core components in the PcG. The gene is highly conserved in organisms ranging from plants to humans, however, the specific function is not well known. The main tasks of this thesis was to investigate the function of Su(z)12 and its expression at different stages of Drosophila development.

In polytene chromosomes of larval salivary glands, Su(z)12 binds to about 90 specific euchromatic sites. The binding along the chromosome arms is mostly in interbands, which are the most DNA de-condensed regions. The binding sites of Su(z)12 in polytene chromosomes correlate precisely with those of the Enhancer-of-zeste (E(z)) protein, indicating that Su(z)12 mainly exists within the Polycomb Repressive Complex 2 (PRC2). However, the binding pattern does not overlap well with Histone 3 lysine 27 tri-methylations (H3K27me3), the specific chromatin mark created by PRC2. The Su(z)12 binding to chromatin is dynamically regulated during mitotic and meiotic cell division. The two different Su(z)12 isoforms: Su(z)12-A and Su(z)12-B (resulting from alternative RNA splicing), have very different expression patterns during development. Functional analyses indicate that they also have different functions he Su(z)12-B form is the main mediator of silencing. Furthermore, a neuron specific localization pattern in larval brain and a giant larval phenotype in transgenic lines reveal a potential function of Su(z)12-A in neuron development.  In some aspects the isoforms seem to be able to substitute for each other.

The histone methyltransferase activity of PRC2 is due to the E(z) protein. However, Su(z)12 is also necessary for H3K27me3 methylation in vivo, and it is thus a core component of PRC2. Clonal over-expression of Su(z)12 in imaginal wing discs results in an increased H3K27me3 activity, indicating that Su(z)12 is a limiting factor for silencing. When PcG function is lost, target genes normally become de-repressed. The segment polarity gene engrailed, encoding a transcription factor, is a target for PRC2 silencing. However, we found that it was not activated when PRC2 function was deleted. We show that the Ultrabithorax protein, encoded by another PcG target gene, also acts as an inhibitor of engrailed and that de-regulation of this gene causes a continued repression of engrailed. The conclusion is that a gene can have several negative regulators working in parallel and that secondary effects have to be taken into consideration, when analyzing effects of mutants.

PcG silencing affects very many cellular processes and a large quantity of knowledge is gathered on the overall mechanisms of PcG regulation. However, little is known about how individual genes are silenced and how cells “remember” their fate through cell generations.

Place, publisher, year, edition, pages
Umeå University: , 2009. 92 p.
Keyword
Epigenetics, histone, polycomb, Drosophila, Suppressor of zeste 12
National Category
Genetics
Research subject
Genetics
Identifiers
urn:nbn:se:umu:diva-18483 (URN)978-91-7264-729-9 (ISBN)
Public defence
2009-03-06, Major Groove, , Molecular Biology Department, Umeå University, Byggnad 6L, 10:00 (English)
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Supervisors
Available from: 2009-02-13 Created: 2009-02-10 Last updated: 2009-02-20Bibliographically approved

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