title: ZNF750 is a p63 target gene that induces KLF4 to drive terminal epidermal differentiation.
abstract: Disrupted epidermal differentiation characterizes numerous diseases that impact >25% of the population. In a search for dominant mediators of differentiation, we defined a requirement for ZNF750 in terminal epidermal differentiation. ZNF750 controlled genes mutated in numerous human skin diseases, including FLG, LOR, LCE3B, ALOXE3, and SPINK5. ZNF750 induced progenitor differentiation via an evolutionarily conserved C2H2 zinc finger motif. The epidermal master regulator, p63, bound the ZNF750 promoter and was necessary for its induction. ZNF750 restored differentiation to p63-deficient tissue, suggesting that it acts downstream of p63. A search for functionally important ZNF750 targets via analysis of ZNF750-regulated genes identified KLF4, a transcription factor that activates late epidermal differentiation. ZNF750 binds to KLF4 at multiple sites flanking the transcriptional start site and controls its expression. ZNF750 thus directly links a tissue-specifying factor, p63, to an effector of terminal differentiation, KLF4, and represents a potential future target for disorders of this process.
authors.affiliation: Department of Medicine/Cellular and Molecular Medicine, University of California-San Diego School of Medicine, La Jolla, CA 92093, USA.
authors.forename: George L
authors.initials: GL
authors.lastname: Sen
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Boxer
authors.forename: Dan E
authors.initials: DE
authors.lastname: Webster
authors.forename: Rose T
authors.initials: RT
authors.lastname: Bussat
authors.forename: Kun
authors.initials: K
authors.lastname: Qu
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Zarnegar
authors.forename: Danielle
authors.initials: D
authors.lastname: Johnston
authors.forename: Zurab
authors.initials: Z
authors.lastname: Siprashvili
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
mesh_terms: D000595:Amino Acid Sequence; D002454:Cell Differentiation; D002478:Cells, Cultured; D000078404:Epidermal Cells; D004817:Epidermis / Q000378:metabolism; D000091344:Filaggrin Proteins; D052816:Foreskin / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D015603:Keratinocytes / Q000502:physiology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000502:physiology*; D008969:Molecular Sequence Data; D014157:Transcription Factors / Q000502:physiology*; D025521:Tumor Suppressor Proteins
chemical_list: C081876:CKAP4 protein, human; C000717249:FLG protein, human; D000091344:Filaggrin Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C570799:ZNF750 protein, human