Genome-Wide Profiling of p63 DNA-Binding Sites Identifies an Element that Regulates Gene Expression during Limb Development in the 7q21 SHFM1 Locus: e1001065

Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-...

Full description

Saved in:
Bibliographic Details
Published in:PLoS genetics 2010-08, Vol.6 (8)
Main Authors: Kouwenhoven, Evelyn N, Heeringen, Simon Jvan, Tena, Juan J, Oti, Martin, Dutilh, Bas E, Alonso, M Eva, Calle-Mustienes, Elisa dela, Smeenk, Leonie, Rinne, Tuula, Parsaulian, Lilian, Bolat, Emine, Jurgelenaite, Rasa, Huynen, Martijn A, Hoischen, Alexander, Veltman, Joris A, Brunner, Han G, Roscioli, Tony, Oates, Emily, Wilson, Meredith, Manzanares, Miguel, Gómez-Skarmeta, José Luis, Stunnenberg, Hendrik G, Lohrum, Marion, Bokhoven, Hans van, Zhou, Huiqing
Format: Article
Language:English
Subjects:
Binding sites
Gene expression
Genetics
Mutation
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-wide DNA-binding profiling by chromatin immunoprecipitation (ChIP), followed by deep sequencing (ChIP-seq) in primary human keratinocytes, and identified potential target genes and regulatory elements controlled by p63. We show that p63 binds to an enhancer element in the SHFM1 locus on chromosome 7q and that this element controls expression of DLX6 and possibly DLX5, both of which are important for limb development. A unique micro-deletion including this enhancer element, but not the DLX5/DLX6 genes, was identified in a patient with SHFM. Our study strongly indicates disruption of a non-coding cis-regulatory element located more than 250 kb from the DLX5/DLX6 genes as a novel disease mechanism in SHFM1. These data provide a proof-of-concept that the catalogue of p63 binding sites identified in this study may be of relevance to the studies of SHFM and other congenital malformations that resemble the p63-associated phenotypes.
ISSN:1553-7390
1553-7404
DOI:10.1371/journal.pgen.1001065