PgmNr D1464: Whole genome analysis of the transcriptional corepressor, Atrophin, reveals interactions with Trithorax-like and regulation of Dpp and Notch signaling.

Authors:
K. Yeung 1,2 ; D. Yap 3 ; P. H. Holmqvist 4 ; A. Boija 4 ; M. Moksa 5 ; S. Aparicio 3 ; M. Fanto 6 ; M. Hirst 5 ; M. Mannervik 4 ; H. McNeill 1,2


Institutes
1) Lunenfeld-Tananbaum Research Institute, Toronto, CA; 2) Department of Molecular Genetics, University of Toronto, Toronto, CA; 3) Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, CA; 4) Department of Molecular Biosciences, The Wenner Gren Institute, Stockholm University, Stockholm, Sweden; 5) Department of Microbiology & Immunology, University of British Columbia, Vancouver, CA; 6) MRC Centre for Developmental Neurobiology, King's College London, Guy's Campus, London, UK.


Keyword: repressors/corepressors

Abstract:

Atrophin (Atro, also known as Grunge) is a transcriptional corepressor. Mutation of a mammalian Atro homolog, Atrophin-1, causes a neurodegenerative disease called dentatorubral-pallidoluysian atrophy in humans, while mutation of the second mammalian Atro homolog, Atrophin-2, causes severe developmental defects. Although Drosophila Atro mutants have a large range of phenotypes including neurodegeneration, segmentation and planar polarity defects, very little is known about Atro’s binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against Atro. Our Atro ChIP-seq identified 1300 potential targets of Atro; these include engrailed, and components of the dpp and Notch signaling pathways.  Using Atro mutant clones, we show that Atro regulates dpp signaling and the expression of Engrailed in imaginal discs. Interestingly, Atro mutant imaginal disc clones have similar phenotypes to the ones caused by loss of Notch signaling. In addition, our bioinformatic analyses, sequential ChIP and coimmunoprecipitation experiments show that Atro and Trithorax-like (Trl, Drosophila GAGA factor) physically interact and bind to the same loci. Atro and Trl also interact genetically. We propose that Atro and Trl function together as a complex to regulate transcription.



Flybase Genetic Index:
1. FlyBase gene symbol: Gug; FBgn: FBgn0010825
2. FlyBase gene symbol: Atro; FBgn: FBgn0010825
3. FlyBase gene symbol: Trl; FBgn: FBgn0013263
4. FlyBase gene symbol: en; FBgn: FBgn0000577
5. FlyBase gene symbol: N; FBgn: FBgn0004647
6. FlyBase gene symbol: dpp; FBgn: FBgn0000490