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pmid: 20808887
pmc: PMC2924305
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.
Male, animal cell, cleft lip, gene targeting, Mice, Child, Cells, Cultured, Cancer, Cultured, cleft face, gene expression regulation, Child, Preschool, anzsrc-for: 3102 Bioinformatics and Computational Biology, Chromosomes, Human, Pair 7, Human, enhancer region, Enhancer Elements, 572, phenotype, Cells, congenital malformation, DCN 2: Functional Neurogenomics, Molecular Sequence Data, Limb Deformities, Congenital, embryo, keratinocyte, chromatin immunoprecipitation, gene sequence, 3105 Genetics, animal tissue, Cancer Genomics, IGMD 3: Genomic disorders and inherited multi-system disorders, Genetic, SDG 3 - Good Health and Well-being, Genetics, case report, Humans, human, Molecular Biology, protein expression, binding site, human cell, Congenital Structural Anomalies, NCMLS 4: Energy and redox metabolism, 31 Biological Sciences, Transcription Factors, Keratinocytes, QH426-470, NCMLS 6: Genetics and epigenetic pathways of disease, 3102 Bioinformatics and Computational Biology, Congenital, 2.1 Biological and endogenous factors, Developmental, gene mutation, anzsrc-for: 31 Biological Sciences, Zebrafish, transcription factor, Pediatric, article, Gene Expression Regulation, Developmental, unclassified drug, DNA-Binding Proteins, Limb Deformities, female, Enhancer Elements, Genetic, congenital skin disease, Pair 7, Female, IGMD 8: Mitochondrial medicine, gene disruption, Biotechnology, Protein Binding, transcription factor DLX6, Research Article, transcription factor DLX5, Proteasome Endopeptidase Complex, Chromatin Immunoprecipitation, gene locus, anzsrc-for: 0604 Genetics, protein DNA binding, Chromosomes, cis acting element, chromosome 7q, heterozygosity, Animals, Preschool, gene identification, Homeodomain Proteins, nonhuman, Binding Sites, Base Sequence, gene deletion, Human Genome, Data Science, Membrane Proteins, nucleotide sequence, protein p63, anzsrc-for: 3105 Genetics, Gene Expression Regulation, ectrodactyly, limb development, Genome-Wide Association Study
Male, animal cell, cleft lip, gene targeting, Mice, Child, Cells, Cultured, Cancer, Cultured, cleft face, gene expression regulation, Child, Preschool, anzsrc-for: 3102 Bioinformatics and Computational Biology, Chromosomes, Human, Pair 7, Human, enhancer region, Enhancer Elements, 572, phenotype, Cells, congenital malformation, DCN 2: Functional Neurogenomics, Molecular Sequence Data, Limb Deformities, Congenital, embryo, keratinocyte, chromatin immunoprecipitation, gene sequence, 3105 Genetics, animal tissue, Cancer Genomics, IGMD 3: Genomic disorders and inherited multi-system disorders, Genetic, SDG 3 - Good Health and Well-being, Genetics, case report, Humans, human, Molecular Biology, protein expression, binding site, human cell, Congenital Structural Anomalies, NCMLS 4: Energy and redox metabolism, 31 Biological Sciences, Transcription Factors, Keratinocytes, QH426-470, NCMLS 6: Genetics and epigenetic pathways of disease, 3102 Bioinformatics and Computational Biology, Congenital, 2.1 Biological and endogenous factors, Developmental, gene mutation, anzsrc-for: 31 Biological Sciences, Zebrafish, transcription factor, Pediatric, article, Gene Expression Regulation, Developmental, unclassified drug, DNA-Binding Proteins, Limb Deformities, female, Enhancer Elements, Genetic, congenital skin disease, Pair 7, Female, IGMD 8: Mitochondrial medicine, gene disruption, Biotechnology, Protein Binding, transcription factor DLX6, Research Article, transcription factor DLX5, Proteasome Endopeptidase Complex, Chromatin Immunoprecipitation, gene locus, anzsrc-for: 0604 Genetics, protein DNA binding, Chromosomes, cis acting element, chromosome 7q, heterozygosity, Animals, Preschool, gene identification, Homeodomain Proteins, nonhuman, Binding Sites, Base Sequence, gene deletion, Human Genome, Data Science, Membrane Proteins, nucleotide sequence, protein p63, anzsrc-for: 3105 Genetics, Gene Expression Regulation, ectrodactyly, limb development, Genome-Wide Association Study
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