Genome-wide profiling of p63 DNA-binding sites identifies an element that regulates gene expression during limb development in the 7q21 SHFM1 locus

Autor: Rasa Jurgelenaite, M. Eva Alonso, Hans van Bokhoven, Martijn A. Huynen, Tuula Rinne, Emine Bolat, Evelyn N. Kouwenhoven, Tony Roscioli, Lilian Parsaulian, Bas E. Dutilh, Meredith Wilson, Martin Oti, Huiqing Zhou, Juan J. Tena, Joris A. Veltman, Emily C. Oates, José Luis Gómez-Skarmeta, Simon J. van Heeringen, Miguel Manzanares, Han G. Brunner, Elisa de la Calle-Mustienes, Leonie Smeenk, Marion Lohrum, Alexander Hoischen, Hendrik G. Stunnenberg
Přispěvatelé: Fundación Pro CNIC, European Commission, National Foundation for Ectodermal Dysplasias, Ministerio de Ciencia e Innovación (España)
Rok vydání: 2010
Předmět:
Keratinocytes
Male
Cancer Research
Genetics and epigenetic pathways of disease [NCMLS 6]
Mice
GeneralLiterature_REFERENCE(e.g.
dictionaries
encyclopedias
glossaries)
Genetics and Genomics/Genetics of Disease
Cells
Cultured
Zebrafish
Genetics (clinical)
Genetics
Regulation of gene expression
Developmental Biology/Morphogenesis and Cell Biology
Genetics and Genomics/Functional Genomics
Gene Expression Regulation
Developmental
DNA-Binding Proteins
Enhancer Elements
Genetic
Mitochondrial medicine [IGMD 8]
Child
Preschool
Female
Functional Neurogenomics [DCN 2]
Chromosomes
Human
Pair 7
Research Article
Protein Binding
Chromatin Immunoprecipitation
Proteasome Endopeptidase Complex
Energy and redox metabolism [NCMLS 4]
lcsh:QH426-470
Molecular Sequence Data
Limb Deformities
Congenital
Locus (genetics)
Biology
Genomic disorders and inherited multi-system disorders [IGMD 3]
Animals
Humans
Limb development
Enhancer
Transcription factor
Gene
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Homeodomain Proteins
Binding Sites
Base Sequence
Data Science
Membrane Proteins
Genetics and Genomics
DNA binding site
lcsh:Genetics
Genetics and Genomics/Disease Models
Chromatin immunoprecipitation
Developmental Biology
Genome-Wide Association Study
Transcription Factors
Zdroj: Plos Genetics, 6, e1001065-e1001065
PLoS Genetics, Vol 6, Iss 8, p e1001065 (2010)
Plos Genetics, 6, 8, pp. e1001065-e1001065
Digital.CSIC. Repositorio Institucional del CSIC
instname
Plos Genetics, 6, 8
Plos Genetics, 6
PLoS Genetics
ISSN: 1553-7404
Popis: 15 páginas, 5 figuras, 3 tablas.-- This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.
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.
This work was supported by EU: EPISTEM FP6-2004-LIFESCIHEALTH-5, Integrated Project LSH-1.2.1-3; National Foundation for Ectodermal Dysplasias USA, 2009; the Spanish Government: BFU2007-60042/BMC, Petri PET2007_0158, Proyecto de Excelencia CVI-3488, BFU2008-00838, and CSD2007-00008; and the ProCNIC Foundation.
Databáze: OpenAIRE
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