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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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© 2013 by Cold Spring Harbor Laboratory Press
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 Urheber:
Ibrahim, Daniel1, Autor           
Hansen, Peter, Autor
Rödelsperger, Christian, Autor
Stiege, Asita C.1, Autor           
Doelken, Sandra C., Autor
Horn, Denise, Autor
Jäger, Marten, Autor
Janetzki, Catrin, Autor
Krawitz, Peter, Autor
Leschik, Gundula, Autor
Wagner, Florian, Autor
Scheuer, Till, Autor
Schmidt-von Kegler, Mareen, Autor
Seemann, Petra, Autor
Timmermann, Bernd2, Autor           
Robinson, Peter N., Autor
Mundlos, Stefan1, Autor           
Hecht, Jochen1, Autor           
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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 Zusammenfassung: 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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Sprache(n): eng - English
 Datum: 2013-08-302013-12
 Publikationsstatus: Erschienen
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 Art der Begutachtung: Expertenbegutachtung
 Identifikatoren: DOI: 10.1101/gr.157610.113
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Titel: Genome Research
Genre der Quelle: Zeitschrift
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Ort, Verlag, Ausgabe: Cold Spring Harbor, N.Y. : Cold Spring Harbor Laboratory Press
Seiten: - Band / Heft: 23 (12) Artikelnummer: - Start- / Endseite: 2091 - 2102 Identifikator: ISSN: 1088-9051
CoNE: https://pure.mpg.de/cone/journals/resource/954926997202