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

Content Provider	PubMed Central
Author	Ibrahim, Daniel M. Hansen, Peter Christian, Rödelsperger Stiege, Asita C. Doelken, Sandra C. Horn, Denise Jäger, Marten Janetzki, Catrin Krawitz, Peter Leschik, Gundula Wagner, Florian Scheuer, Till Kegler, Mareen Schmidt-von Seemann, Petra Timmermann, Bernd Robinson, Peter N. Stefan, Mundlos Hecht, Jochen
Copyright Year	2013
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.
Related Links	http://dx.doi.org/10.1101/gr.157610.113
Ending Page	2102
Page Count	12
Starting Page	2091
File Format	PDF
ISSN	10889051
e-ISSN	15495469
Journal	Genome Research
Issue Number	12
Volume Number	23
Language	English
Publisher	Cold Spring Harbor Laboratory Press
Publisher Date	2013-12-01
Access Restriction	Open
Rights Holder	Cold Spring Harbor Laboratory Press
Subject Keyword	Genetics(clinical) Genetics Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Genetics Genetics (clinical)

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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