title: A composite enhancer regulates p63 gene expression in epidermal morphogenesis and in keratinocyte differentiation by multiple mechanisms.
abstract: p63 is a crucial regulator of epidermal development, but its transcriptional control has remained elusive. Here, we report the identification of a long-range enhancer (p63LRE) that is composed of two evolutionary conserved modules (C38 and C40), acting in concert to control tissue- and layer-specific expression of the p63 gene. Both modules are in an open and active chromatin state in human and mouse keratinocytes and in embryonic epidermis, and are strongly bound by p63. p63LRE activity is dependent on p63 expression in embryonic skin, and also in the commitment of human induced pluripotent stem cells toward an epithelial cell fate. A search for other transcription factors involved in p63LRE regulation revealed that the CAAT enhancer binding proteins Cebpa and Cebpb and the POU domain-containing protein Pou3f1 repress p63 expression during keratinocyte differentiation by binding the p63LRE enhancer. Collectively, our data indicate that p63LRE is composed of additive and partly redundant enhancer modules that act to direct robust p63 expression selectively in the basal layer of the epidermis.
authors.affiliation: IRCCS SDN, Napoli, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Antonini
authors.affiliation: CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Sirico
authors.affiliation: INSERM UMR-S 976, Paris, France Université Paris-Diderot, Hopital St-Louis, Paris, France.
authors.forename: Edith
authors.initials: E
authors.lastname: Aberdam
authors.affiliation: IRCCS SDN, Napoli, Italy.
authors.forename: Raffaele
authors.initials: R
authors.lastname: Ambrosio
authors.affiliation: CEINGE Biotecnologie Avanzate, Napoli, Italy.
authors.forename: Carmen
authors.initials: C
authors.lastname: Campanile
authors.affiliation: Institute for Biostructures and Bioimages (CNR), c/o Molecular Biotechnology Center, University of Turin, Torino, Italy.
authors.forename: Sharmila
authors.initials: S
authors.lastname: Fagoonee
authors.affiliation: Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, Torino, Italy.
authors.forename: Fiorella
authors.initials: F
authors.lastname: Altruda
authors.affiliation: INSERM UMR-S 976, Paris, France Université Paris-Diderot, Hopital St-Louis, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Aberdam
authors.affiliation: Department of Cell Biology, State University of New York Downstate Medical Center, NY, USA.
authors.forename: Janice L
authors.initials: JL
authors.lastname: Brissette
authors.affiliation: CEINGE Biotecnologie Avanzate, Napoli, Italy Department of Biology, University of Naples Federico II, Napoli, Italy caterina.missero@unina.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Missero
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004742:Enhancer Elements, Genetic; D004817:Epidermis / Q000196:embryology* / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009024:Morphogenesis / Q000235:genetics; D010750:Phosphoproteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D010750:Phosphoproteins; D015534:Trans-Activators; D014157:Transcription Factors; C486419:Trp63 protein, mouse