Atrophin controls developmental signaling pathways via interactions with Trithorax-like.
Mutations in humanAtrophin1, a transcriptional corepressor, cause dentatorubral-pallidoluysian atrophy, a neurodegenerative disease.Drosophila Atrophin(Atro) mutants display many phenotypes, including neurodegeneration, segmentation, patterning and planar polarity defects. Despite Atro's critical role in development and disease, relatively little is known about Atro's binding partners and downstream targets. We present the first genomic analysis of Atro using ChIP-seq against endogenous Atro. ChIP-seq identified 1300 potential direct targets of Atro includingengrailed, and components of the Dpp and Notch signaling pathways. We show that Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation ofthickveinsandfringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with theDrosophilaGAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses ofTrlandAtroclones suggest that Atro is required to modulate the transcription activation by Trl in larval imaginal discs. Taken together, these data indicate that Atro is a major Trl cofactor that functions to moderate developmental gene transcription.
Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
Kelvin
http://orcid.org/0000-0003-2284-8734
K
Yeung
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Ann
A
Boija
Department of Molecular Biology, Umeå University, Umeå, Sweden.|Division of CBRN Security and Defence, FOI-Swedish Defence Research Agency, Umeå, Sweden.
Edvin
E
Karlsson
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Per-Henrik
PH
Holmqvist
Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
Yonit
Y
Tsatskis
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, United Kingdom.
Ilaria
I
Nisoli
Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Damian
http://orcid.org/0000-0002-5370-4592
D
Yap
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.|Michael Smith Laboratories, Vancouver, Canada.|Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada.
Alireza
A
Lorzadeh
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.|Michael Smith Laboratories, Vancouver, Canada.|Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada.
Michelle
M
Moksa
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada.|Michael Smith Laboratories, Vancouver, Canada.|Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, Canada.
Martin
M
Hirst
Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
Samuel
S
Aparicio
Department of Basic and Clinical Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King's College London, London, United Kingdom.
Manolis
M
Fanto
Department of Molecular Biology, Umeå University, Umeå, Sweden.|Division of CBRN Security and Defence, FOI-Swedish Defence Research Agency, Umeå, Sweden.
Per
P
Stenberg
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
Mattias
M
Mannervik
Department of Molecular Genetics, University of Toronto, Toronto, Canada.|Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.
Helen
http://orcid.org/0000-0003-1126-5154
H
McNeill
D000818:Animals; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004330:Drosophila / Q000196:embryology*; D029721:Drosophila Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D025941:Protein Interaction Mapping; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D014157:Transcription Factors; C063460:Trl protein, Drosophila; C450826:gug protein, Drosophila
Atrophin; D. melanogaster; Dpp signaling; GAGA Factor / Trithorax-like; Notch signaling; chromosomes; developmental biology; engrailed; genes; stem cells