Atrophin controls developmental signaling pathways via interactions with Trithorax-like
- University of Toronto, Canada
- Stockholm University, Sweden
- Umeå University, Sweden
- University College London, United Kingdom
- University of British Columbia, Canada
- King's College London, United Kingdom
Abstract
Mutations in human Atrophin1, 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 including engrailed, and components of the Dpp and Notch signaling pathways. We show Atro regulates Dpp and Notch signaling in larval imaginal discs, at least partially via regulation of thickveins and fringe. In addition, bioinformatics analyses, sequential ChIP and coimmunoprecipitation experiments reveal that Atro interacts with the Drosophila GAGA Factor, Trithorax-like (Trl), and they bind to the same loci simultaneously. Phenotypic analyses of Trl and Atro clones 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.
Data availability
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ChIP-seq of Atrophin in Drosophila S2 cellsPublicly available at the NCBI Gene (accession no: GSE87509).
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Atrophin (Atro) ChIP-seq data from Drosophila S2 cellsPublicly available at the NCBI Gene (accession no: GSE87471).
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Chromatin Binding Site Mapping of Transcription Factors in D. melanogaster by ChIP-seqPublicly available at Modencode (http://intermine.modencode.org).
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Chromatin Binding Site MappingPublicly available at Modencode (http://intermine.modencode.org).
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The Genomic Binding Profile of GAGA Element Associated Factor (GAF) in Drosophila S2 cellsPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE40646).
Article and author information
Author details
Funding
Canadian Institutes of Health Research (FDN 143319)
- Helen McNeill
Medical Research Council (NIRG-G1002186)
- Manolis Fanto
Knut och Alice Wallenbergs Stiftelse
- Per Stenberg
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Yeung et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Atrophin controls developmental signaling pathways via interactions with Trithorax-like
eLife 6:e23084.
https://doi.org/10.7554/eLife.23084
Further reading
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- Cell Biology
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Long thought to have little relevance to ovarian physiology, the rete ovarii may have a role in follicular dynamics and reproductive health.
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- Cell Biology
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The rete ovarii (RO) is an appendage of the ovary that has been given little attention. Although the RO appears in drawings of the ovary in early versions of Gray’s Anatomy, it disappeared from recent textbooks, and is often dismissed as a functionless vestige in the adult ovary. Using PAX8 immunostaining and confocal microscopy, we characterized the fetal development of the RO in the context of the mouse ovary. The RO consists of three distinct regions that persist in adult life, the intraovarian rete (IOR), the extraovarian rete (EOR), and the connecting rete (CR). While the cells of the IOR appear to form solid cords within the ovary, the EOR rapidly develops into a convoluted tubular epithelium ending in a distal dilated tip. Cells of the EOR are ciliated and exhibit cellular trafficking capabilities. The CR, connecting the EOR to the IOR, gradually acquires tubular epithelial characteristics by birth. Using microinjections into the distal dilated tip of the EOR, we found that luminal contents flow toward the ovary. Mass spectrometry revealed that the EOR lumen contains secreted proteins potentially important for ovarian function. We show that the cells of the EOR are closely associated with vasculature and macrophages, and are contacted by neuronal projections, consistent with a role as a sensory appendage of the ovary. The direct proximity of the RO to the ovary and its integration with the extraovarian landscape suggest that it plays an important role in ovary development and homeostasis.
