Genome-wide chromatin accessibility and transcriptome profiling show minimal epigenome changes and coordinated transcriptional dysregulation of hedgehog signaling in Danforth’s short tail mice
| Autor: | James S. White, John Hensley, Benjamin L. Allen, Catherine E. Keegan, Anya Kiseleva, Peter Orchard, Peedikayil E. Thomas, Stephen C. J. Parker, Anna Mychalowych |
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| Rok vydání: | 2018 |
| Předmět: |
Organogenesis
Fluorescent Antibody Technique Transcriptome Epigenome Mice 03 medical and health sciences 0302 clinical medicine Genetics Animals Hedgehog Proteins Sonic hedgehog Promoter Regions Genetic Enhancer Molecular Biology Genetics (clinical) 030304 developmental biology Epigenomics 0303 health sciences biology Gene Expression Profiling 030305 genetics & heredity Computational Biology General Medicine Chromatin Assembly and Disassembly Chromatin Hedgehog signaling pathway Cell biology Enhancer Elements Genetic Gene Ontology Phenotype Gene Expression Regulation Mutation biology.protein Ectopic expression General Article Biomarkers 030217 neurology & neurosurgery Signal Transduction |
| DOI: | 10.1101/387977 |
| Popis: | Danforth’s short tail(Sd)mice provide an excellent model for investigating the underlying etiology of human caudal birth defects, which affect 1 in 10,000 live births.Sdanimals exhibit aberrant axial skeleton, urogenital, and gastrointestinal development similar to human caudal malformation syndromes including urorectal septum malformation, caudal regression, VACTERL association, and persistent cloaca. Previous studies have shown that theSdmutation results from an endogenous retroviral (ERV) insertion upstream of thePtf1agene resulting in its ectopic expression at E9.5. Though the genetic lesion has been determined, the resulting epigenomic and transcriptomic changes driving the phenotype have not been investigated. Here, we performed ATAC-seq experiments on isolated E9.5 tailbud tissue, which revealed minimal changes in chromatin accessibility inSd/Sdmutant embryos. Interestingly, chromatin changes were localized to a small interval adjacent to theSdERV insertion overlapping a knownPtf1aenhancer region, which is conserved in mice and humans. Furthermore, mRNA-seq experiments revealed increased transcription of PTF1A target genes and, importantly, downregulation of hedgehog pathway genes. Reduced sonic hedgehog (SHH) signaling was confirmed by in situ hybridization and immunofluorescence suggesting that theSdphenotype results, in part, from downregulated SHH signaling. Taken together, these data demonstrate substantial transcriptome changes in theSdmouse, and indicate that the effect of the ERV insertion onPtf1aexpression may be mediated by increased chromatin accessibility at a conservedPtf1aenhancer. We propose that human caudal dysgenesis disorders may result from dysregulation of hedgehog signaling pathways. |
| Databáze: | OpenAIRE |
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