title: ZNF750 interacts with KLF4 and RCOR1, KDM1A, and CTBP1/2 chromatin regulators to repress epidermal progenitor genes and induce differentiation genes.
abstract: ZNF750 controls epithelial homeostasis by inhibiting progenitor genes while inducing differentiation genes, a role underscored by pathogenic ZNF750 mutations in cancer and psoriasis. How ZNF750 accomplishes these dual gene regulatory impacts is unknown. Here, we characterized ZNF750 as a transcription factor that binds both the progenitor and differentiation genes that it controls at a CCNNAGGC DNA motif. ZNF750 interacts with the pluripotency transcription factor KLF4 and chromatin regulators RCOR1, KDM1A, and CTBP1/2 through conserved PLNLS sequences. ChIP-seq (chromatin immunoprecipitation [ChIP] followed by high-throughput sequencing) and gene depletion revealed that KLF4 colocalizes ∼ 10 base pairs from ZNF750 at differentiation target genes to facilitate their activation but is unnecessary for ZNF750-mediated progenitor gene repression. In contrast, KDM1A colocalizes with ZNF750 at progenitor genes and facilitates their repression but is unnecessary for ZNF750-driven differentiation. ZNF750 thus controls differentiation in concert with RCOR1 and CTBP1/2 by acting with either KDM1A to repress progenitor genes or KLF4 to induce differentiation genes.
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA; Department of Biology, Stanford University, Stanford, California 94305, USA;
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Boxer
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Brook
authors.initials: B
authors.lastname: Barajas
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Shiying
authors.initials: S
authors.lastname: Tao
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA;
authors.forename: Jiajing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA; Veterans Affairs Palo Alto Healthcare System, Palo Alto, California 94304, USA khavari@stanford.edu.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D002874:Chromosome Mapping; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; C000715467:KLF4 protein, human; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C121019:RCOR1 protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C570799:ZNF750 protein, human; D000429:Alcohol Oxidoreductases; C421248:CTBP2 protein, human; C096794:C-terminal binding protein; D056466:Histone Demethylases; C495195:KDM1A protein, human
keywords: KLF4; ZNF750; chromatin regulator; differentiation; stem cell