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Drosophila Brakeless interacts with Atrophin and is required for Tailless-mediated transcriptional repression in early embryos
Stockholm University, Faculty of Science, The Wenner-Gren Institute .
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2007 (English)In: PLoS biology, ISSN 1544-9173, E-ISSN 1545-7885, Vol. 5, no 6Article in journal (Refereed) Published
Abstract [en]

Complex gene expression patterns in animal development are generated by the interplay of transcriptional activators and repressors at cis-regulatory DNA modules (CRMs). How repressors work is not well understood, but often involves interactions with co-repressors. We isolated mutations in the brakeless gene in a screen for maternal factors affecting segmentation of the Drosophila embryo. Brakeless, also known as Scribbler, or Master of thickveins, is a nuclear protein of unknown function. In brakeless embryos, we noted an expanded expression pattern of the Krüppel (Kr) and knirps (kni) genes. We found that Tailless-mediated repression of kni expression is impaired in brakeless mutants. Tailless and Brakeless bind each other in vitro and interact genetically. Brakeless is recruited to the Kr and kni CRMs, and represses transcription when tethered to DNA. This suggests that Brakeless is a novel co-repressor. Orphan nuclear receptors of the Tailless type also interact with Atrophin co-repressors. We show that both Drosophila and human Brakeless and Atrophin interact in vitro, and propose that they act together as a co-repressor complex in many developmental contexts. We discuss the possibility that human Brakeless homologs may influence the toxicity of polyglutamine-expanded Atrophin-1, which causes the human neurodegenerative disease dentatorubral-pallidoluysian atrophy (DRPLA).

Place, publisher, year, edition, pages
Haecker et al , 2007. Vol. 5, no 6
National Category
Biological Sciences
URN: urn:nbn:se:su:diva-24252DOI: 10.1371/journal.pbio.0050145OAI: diva2:197105
Part of urn:nbn:se:su:diva-6817Available from: 2007-05-24 Created: 2007-05-02 Last updated: 2010-12-14Bibliographically approved
In thesis
1. Functions of Transcriptional Co-regulators in Drosophila development
Open this publication in new window or tab >>Functions of Transcriptional Co-regulators in Drosophila development
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During Drosophila development, regulation of gene expression through interplay between transcriptional activators and repressors is generating complex patterns of gene expression that leads to cell differentiation. For proper control of transcription, transcription factors bind to DNA at control regions, so called Cis Regulatory Modules (CRM). Transcription factors recruit additional factors, co-regulators, that affect gene expression through interactions with the general transcription machinery, as well as affect the chromatin environment through post-translational modifications of the histone tails. In this thesis the role of transcriptional co-regulators in Drosophila development is investigated.

This work has demonstrated the need for the transcriptional co-activator CREB binding protein (CBP) in signalling by the Transforming Growth Factor-β (TGF-β) molecules Decapentaplegic (Dpp) and Screw (Scw) in early embryos. Furthermore it is shown that the acetyl transferase activity of CBP is dispensable for this function.

In a screen for novel regulators of gene expression in the embryo, Brakeless (Bks) was isolated as a co-repressor for the Tailless (Tll) transcription factor. This work shows that Tll function is impaired in bks mutants, that Bks and Tll bind each other in vitro and interact genetically. Bks is present on CRMs controlled by Tll and can repress transcription when tethered to DNA. Bks interacts and functions together with another co-repressor Atrophin.

Reptin is part of several complexes including the TIP60 Histone Acetyl Transferase (HAT) complex. Work in this thesis show that Reptin and other members of the TIP60 complex function in formation of silent chromatin in Drosophila.

Together these results show that transcriptional co-regulators function selectively in specific processes during development.

Place, publisher, year, edition, pages
Stockholm: Wenner-Grens institut för experimentell biologi, 2007. 75 p.
Transcription, Co-regulator, Development, Drosophila
National Category
Developmental Biology
Research subject
Developmental Biology
urn:nbn:se:su:diva-6817 (URN)978-91-7155-436-9 (ISBN)
Public defence
2007-06-14, De Geersalen, Geovetenskapens hus, Svante Arrhenius väg 8 A, Stockholm, 10:00
Available from: 2007-05-24 Created: 2007-05-02Bibliographically approved

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Mannervik, Mattias
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