Genomic Profiling of a Human Organotypic Model of AEC Syndrome Reveals ZNF750 as an Essential Downstream Target of Mutant TP63
| Autor: | Paul A. Khavari, David R. Berk, Karen J. Yan, Brook Vander Stoep Hunt, George L. Sen, Brian J. Zarnegar, Dan E. Webster, Vanessa Lopez-Pajares, Kun Qu |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
Cellular differentiation
Cleft Lip Mutant education Biology Article Transcriptome 03 medical and health sciences Kruppel-Like Factor 4 0302 clinical medicine Organ Culture Techniques Downregulation and upregulation Ectodermal Dysplasia Genetics Humans Genetics(clinical) Eye Abnormalities Transcription factor Genetics (clinical) 030304 developmental biology 0303 health sciences Activator (genetics) Tumor Suppressor Proteins Eyelids Cell Differentiation respiratory system Cell biology Cleft Palate KLF4 030220 oncology & carcinogenesis Mutation Epidermis Chromatin immunoprecipitation Transcription Factors |
| Popis: | The basis for impaired differentiation in TP63 mutant ankyloblepharon-ectodermal dysplasia-clefting (AEC) syndrome is unknown. Human epidermis harboring AEC TP63 mutants recapitulated this impairment, along with downregulation of differentiation activators, including HOPX, GRHL3, KLF4, PRDM1, and ZNF750. Gene-set enrichment analysis indicated that disrupted expression of epidermal differentiation programs under the control of ZNF750 and KLF4 accounted for the majority of disrupted epidermal differentiation resulting from AEC mutant TP63. Chromatin immunoprecipitation (ChIP) analysis and ChIP-sequencing of TP63 binding in differentiated keratinocytes revealed ZNF750 as a direct target of wild-type and AEC mutant TP63. Restoring ZNF750 to AEC model tissue rescued activator expression and differentiation, indicating that AEC TP63-mediated ZNF750 inhibition contributes to differentiation defects in AEC. Incorporating disease-causing mutants into regenerated human tissue can thus dissect pathomechanisms and identify targets that reverse disease features. |
| Databáze: | OpenAIRE |
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