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  Distinct global shifts in genomic binding profiles of limb malformation associated HOXD13 mutations

Ibrahim, D., Hansen, P., Rödelsperger, C., Stiege, A. C., Doelken, S. C., Horn, D., et al. (2013). Distinct global shifts in genomic binding profiles of limb malformation associated HOXD13 mutations. Genome Research, 23(12), 2091-2102. doi:10.1101/gr.157610.113.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-B07C-F Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0027-B07D-D
Genre: Journal Article

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 Creators:
Ibrahim, Daniel1, Author              
Hansen, Peter, Author
Rödelsperger, Christian, Author
Stiege, Asita C.1, Author              
Doelken, Sandra C., Author
Horn, Denise, Author
Jäger, Marten, Author
Janetzki, Catrin, Author
Krawitz, Peter, Author
Leschik, Gundula, Author
Wagner, Florian, Author
Scheuer, Till, Author
Schmidt-von Kegler, Mareen, Author
Seemann, Petra, Author
Timmermann, Bernd2, Author              
Robinson, Peter N., Author
Mundlos, Stefan1, Author              
Hecht, Jochen1, Author              
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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 Abstract: Gene regulation by transcription factors (TFs) determines developmental programs and cell identity. Consequently, mutations in TFs can lead to dramatic phenotypes in humans by disrupting gene regulation. To date, the molecular mechanisms that actually cause these phenotypes have been difficult to address experimentally. ChIP-seq, which couples chromatin immunoprecipitation with high-throughput sequencing, allows TF function to be investigated on a genome-wide scale, enabling new approaches for the investigation of gene regulation. Here, we present the application of ChIP-seq to explore the effect of missense mutations in TFs on their genome-wide binding profile. Using a retroviral expression system in chicken mesenchymal stem cells, we elucidated the mechanism underlying a novel missense mutation in HOXD13 (Q317K) associated with a complex hand and foot malformation phenotype. The mutated glutamine (Q) is conserved in most homeodomains, a notable exception being bicoid-type homeodomains that have lysine (K) at this position. Our results show that the mutation results in a shift in the binding profile of the mutant toward a bicoid/PITX1 motif. Gene expression analysis and functional assays using in vivo overexpression studies confirm that the mutation results in a partial conversion of HOXD13 into a TF with bicoid/PITX1 properties. A similar shift was not observed with another mutation, Q317R, which is associated with brachysyndactyly, suggesting that the bicoid/PITX1-shift observed for Q317K might be related to the severe clinical phenotype. The methodology described can be used to investigate a wide spectrum of TFs and mutations that have not previously been amenable to ChIP-seq experiments.

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Language(s): eng - English
 Dates: 2013-08-302013-12
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1101/gr.157610.113
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Title: Genome Research
Source Genre: Journal
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Publ. Info: Cold Spring Harbor, N.Y. : Cold Spring Harbor Laboratory Press
Pages: - Volume / Issue: 23 (12) Sequence Number: - Start / End Page: 2091 - 2102 Identifier: ISSN: 1088-9051
CoNE: /journals/resource/954926997202