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The role of Suppressor of zeste 12 in cell cycle regulation
Umeå University, Faculty of Medicine, Molecular Biology. (Åsa Rasmuson-Lestander)
Umeå University, Faculty of Medicine, Molecular Biology. (Åsa Rasmuson-Lestander)
(English)Manuscript (Other academic)
Abstract [en]

Polycomb group (PcG) proteins control a large amount of target genes and are essential for genomic programming and differentiation. Many members in the PcG family have been shown to be upregulated in different types of cancers. Suppressor of zeste 12 (Su(z)12) is an essential component in PcG silencing and is necessary for histone 3 lysine 27 tri-methylation in vivo. To unravel a possible role of Su(z)12 in cell cycle regulation, we first investigate the localization pattern of Su(z)12 in Drosophila wildtype testes and embryos by immunohistochemical staining. We found that Su(z)12 was dynamically regulated during cell division. Further investigation of the function of Su(z)12 in cell division was done by cell number counting, apoptosis and proliferation marker staining in Su(z)12 somatic knockout clones in wing discs. The conclusion from the small wing phenotype in Su(z)12 knockout wing discs is that Su(z)12 may increase apoptosis and decrease cell proliferation rate.

Keyword [en]
Su(z)12, apoptosis, proliferation, cell cycle, mitosis
Identifiers
URN: urn:nbn:se:umu:diva-18651OAI: oai:DiVA.org:umu-18651DiVA: diva2:174307
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)
Opponent
Supervisors
Available from: 2009-02-13 Created: 2009-02-10 Last updated: 2009-02-20Bibliographically approved

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