title: Genomic profiling of a human organotypic model of AEC syndrome reveals ZNF750 as an essential downstream target of mutant TP63.
abstract: 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.
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Zarnegar
authors.forename: Dan E
authors.initials: DE
authors.lastname: Webster
authors.forename: Vanessa
authors.initials: V
authors.lastname: Lopez-Pajares
authors.forename: Brook
authors.initials: B
authors.lastname: Vander Stoep Hunt
authors.forename: Kun
authors.initials: K
authors.lastname: Qu
authors.forename: Karen J
authors.initials: KJ
authors.lastname: Yan
authors.forename: David R
authors.initials: DR
authors.lastname: Berk
authors.forename: George L
authors.initials: GL
authors.lastname: Sen
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
mesh_terms: D002454:Cell Differentiation / Q000235:genetics; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D004476:Ectodermal Dysplasia / Q000235:genetics*; D004817:Epidermis / Q000378:metabolism; D005124:Eye Abnormalities / Q000235:genetics*; D005143:Eyelids / Q000002:abnormalities; D006801:Humans; D000090062:Kruppel-Like Factor 4; D009154:Mutation; D009924:Organ Culture Techniques / Q000379:methods; D014157:Transcription Factors / Q000235:genetics*; D059467:Transcriptome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; C115051:TP63 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C570799:ZNF750 protein, human