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

• DOI: 10.1371/journal.pgen.1001065
• Publication Date: 2010-08-19T21:42:57Z
• Authors: Evelyn N. Kouwenh...; Simon J. van Heer...; Juan J. Tena; Martin Oti; Bas E. Dutilh; M. Eva Alonso; Elisa de la Calle...; Leonie Smeenk; Tuula Rinne; Lilian Parsaulian; Emine Bolat; Rasa Jurgelenaite; Martijn A. Huynen; Alexander Hoischen; Joris A. Veltman; Han G. Brunner; Tony Roscioli; Emily Oates; Meredith Wilson; Miguel Manzanares; José Luis Gómez-S...; Hendrik G. Stunne...; Marion Lohrum; Hans van Bokhoven; Huiqing Zhou
• Keywords: Limb development; Chromatin immunoprecipitation; Chromosome conformation capture; DLX5

Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the gene network that includes target genes regulatory elements may reveal new for other malformation disorders. We performed genome-wide DNA-binding profiling by chromatin immunoprecipitation (ChIP), followed deep sequencing (ChIP-seq) primary human keratinocytes, identified potential controlled p63. show binds to an enhancer element SHFM1 locus on chromosome 7q this controls expression DLX6 possibly DLX5, both which important limb development. A unique micro-deletion including element, but not DLX5/DLX6 genes, was a patient SHFM. Our study strongly indicates disruption non-coding cis-regulatory located more than 250 kb from as novel disease mechanism SHFM1. These data provide proof-of-concept catalogue binding sites be relevance studies SHFM congenital resemble p63-associated phenotypes.