title: Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4.
abstract: Human epidermal stem cells transit from a slow cycling to an actively proliferating state to contribute to homeostasis. Both stem cell states differ in their cell cycle profiles but must remain guarded from differentiation and senescence. Here we show that Cbx4, a Polycomb Repressive Complex 1 (PRC1)-associated protein, maintains human epidermal stem cells as slow-cycling and undifferentiated, while protecting them from senescence. Interestingly, abrogating the polycomb activity of Cbx4 impairs its antisenescent function without affecting stem cell differentiation, indicating that differentiation and senescence are independent processes in human epidermis. Conversely, Cbx4 inhibits stem cell activation and differentiation through its SUMO ligase activity. Global transcriptome and chromatin occupancy analyses indicate that Cbx4 regulates modulators of epidermal homeostasis and represses factors such as Ezh2, Dnmt1, and Bmi1 to prevent the active stem cell state. Our results suggest that distinct Polycomb complexes balance epidermal stem cell dormancy and activation, while continually preventing senescence and differentiation.
authors: Center for Genomic Regulation (CRG) and UPF, 08003, Barcelona, Spain.
authors: Nuno Miguel
authors: NM
authors: Luis
authors: Lluis
authors: L
authors: Morey
authors: Stefania
authors: S
authors: Mejetta
authors: Gloria
authors: G
authors: Pascual
authors: Peggy
authors: P
authors: Janich
authors: Bernd
authors: B
authors: Kuebler
authors: Luca
authors: L
authors: Cozutto
authors: Guglielmo
authors: G
authors: Roma
authors: Elisabete
authors: E
authors: Nascimento
authors: Michaela
authors: M
authors: Frye
authors: Luciano
authors: L
authors: Di Croce
authors: Salvador Aznar
authors: SA
authors: Benitah
mesh_terms: D000328:Adult; D053687:Adult Stem Cells / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000235:genetics; D042002:Chromatin Assembly and Disassembly; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D004817:Epidermis / Q000473:pathology; D052816:Foreskin / Q000473:pathology; D020869:Gene Expression Profiling; D006801:Humans; D007231:Infant, Newborn; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008025:Ligases; D008297:Male; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases
chemical_list: C069077:BMI1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D025842:SUMO-1 Protein; D014157:Transcription Factors; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; D044767:Ubiquitin-Protein Ligases; D008025:Ligases; C570427:CBX4 protein, human