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| Status |
Public on Jul 04, 2017 |
| Title |
A multipartite enhancer ensemble coordinates pleiotropic developmental functions of Indian hedgehog |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
Copy number variations (CNVs) including enhancers frequently appear associated with disease, induced by pathomechanisms that are poorly understood. Here we show through transgenic reporter and genome editing studies in mice that Indian hedgehog (Ihh) is regulated by a constellation of enhancers of unusual complexity and we uncover how duplications within this enhancer architecture cause phenotypes reminiscent of those observed in human patients. At least nine enhancers with distinct combinations of activities orchestrate the expression of Ihh in the digit anlagen, growth plates, skull sutures, and digit tips. Consecutive deletions show that they function in an additive manner resulting in growth defects. Duplications, in contrast, cause not only dose-dependent upregulation of Ihh, but also misexpression, leading to phenotypes influenced by the copy number and relative positioning of individual elements. Taken together, our results uncover a complex regulatory landscape at the Ihh locus and exemplify the intricate and precise control of gene expression during morphogenetic processes.
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| Overall design |
Circular Chromosome Conformation Capture (4C-seq) at the Ihh locus in mouse forelimb tissues (digit 2-5) of mutants and WT animals at E14.5.
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| Contributor(s) |
Will AJ, Heinrich V, Lupiáñez DG, Mundlos S |
| Citation(s) |
28846100 |
| |
| Submission date |
Feb 18, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Darío G Lupiáñez |
| E-mail(s) |
lupianez@molgen.mpg.de
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| Organization name |
Max Planck Institute for Molecular Genetics
|
| Street address |
Ihnestrasse 73
|
| City |
Berlin |
| ZIP/Postal code |
14195 |
| Country |
Germany |
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| Platforms (2) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL18480 |
Illumina HiSeq 1500 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA375879 |
| SRA |
SRP100285 |
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