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
-
ChIP-seq of Atrophin in Drosophila S2 cellsPublicly available at the NCBI Gene (accession no: GSE87509).
-
Atrophin (Atro) ChIP-seq data from Drosophila S2 cellsPublicly available at the NCBI Gene (accession no: GSE87471).
-
Chromatin Binding Site Mapping of Transcription Factors in D. melanogaster by ChIP-seqPublicly available at Modencode (http://intermine.modencode.org).
-
Chromatin Binding Site MappingPublicly available at Modencode (http://intermine.modencode.org).
-
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.
Metrics
-
- 1,467
- views
-
- 373
- downloads
-
- 16
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Atrophin controls developmental signaling pathways via interactions with Trithorax-like
eLife 6:e23084.
https://doi.org/10.7554/eLife.23084
Further reading
-
- Developmental Biology
- Neuroscience
Environmental insults, including mild head trauma, significantly increase the risk of neurodegeneration. However, it remains challenging to establish a causative connection between early-life exposure to mild head trauma and late-life emergence of neurodegenerative deficits, nor do we know how sex and age compound the outcome. Using a Drosophila model, we demonstrate that exposure to mild head trauma causes neurodegenerative conditions that emerge late in life and disproportionately affect females. Increasing age-at-injury further exacerbates this effect in a sexually dimorphic manner. We further identify sex peptide signaling as a key factor in female susceptibility to post-injury brain deficits. RNA sequencing highlights a reduction in innate immune defense transcripts specifically in mated females during late life. Our findings establish a causal relationship between early head trauma and late-life neurodegeneration, emphasizing sex differences in injury response and the impact of age-at-injury. Finally, our findings reveal that reproductive signaling adversely impacts female response to mild head insults and elevates vulnerability to late-life neurodegeneration.
-
- Developmental Biology
- Genetics and Genomics
New developmental programs can evolve through adaptive changes to gene expression. The annelid Streblospio benedicti has a developmental dimorphism, which provides a unique intraspecific framework for understanding the earliest genetic changes that take place during developmental divergence. Using comparative RNAseq through ontogeny, we find that only a small proportion of genes are differentially expressed at any time, despite major differences in larval development and life history. These genes shift expression profiles across morphs by either turning off any expression in one morph or changing the timing or amount of gene expression. We directly connect the contributions of these mechanisms to differences in developmental processes. We examine F1 offspring – using reciprocal crosses – to determine maternal mRNA inheritance and the regulatory architecture of gene expression. These results highlight the importance of both novel gene expression and heterochronic shifts in developmental evolution, as well as the trans-acting regulatory factors in initiating divergence.
