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Title Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4

Authors Nuno Miguel Luis, Lluis Morey, Stefania Mejetta, Gloria Pascual, Peggy Janich, Bernd Kuebler, Luca Cozutto, Guglielmo Roma, Elisabete Nascimento, Michaela Frye, Luciano Di Croce, Salvador Aznar Benitah
Date 2011-09-02

Publisher Cell Stem Cell
DOI 10.1016/j.stem.2011.07.013
Tag Adult, Adult Stem Cells, Cell Differentiation, Cell Proliferation, Cells, Cultured, Cellular Senescence, Chromatin Assembly and Disassembly, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Enhancer of Zeste Homolog 2 Protein, Epidermis, Foreskin, Gene Expression Profiling, Humans, Infant, Newborn, Keratinocytes, Ligases, Male, Mutagenesis, Site-Directed, Nuclear Proteins, Polycomb Repressive Complex 1, Polycomb Repressive Complex 2, Polycomb-Group Proteins, Proto-Oncogene Proteins, RNA, Small Interfering, Repressor Proteins, SUMO-1 Protein, Transcription Factors, Ubiquitin-Protein Ligases

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.

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