Regulation of human epidermal stem cell proliferation and senescence requires polycomb- dependent and -independent functions of Cbx4
Open accessAbstract
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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Activation of the RB tumor suppressive pathway by accumulation of p16 is often considered a key mechanism triggering cell senescence in several systems, including skin keratinocytes.
“The activation of the RB tumor suppressive pathway by the accumulation of p16 is often considered a key mechanism triggering cell senescence in several systems, including skin keratinocytes (Kuilman et al., 2010; Luis et al., 2011).”
From mTOR inhibition prevents epithelial stem cell senescence and protects from radiation-induced mucositis (2012) · cites this paper as Luis et al., 2011
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References 64 · Cited by 142
- Authors
- Luis, N. M., Morey, L., Mejetta, S., Pascual, G., Janich, P., Kuebler, B., Roma, G., Nascimento, E., Frye, M., Di Croce, L., & Benitah, S. A.
- Affiliations
- Centre for Genomic Regulation (ES)
- Wellcome/MRC Cambridge Stem Cell Institute (GB)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Benitah, Salvador Aznar
- ORCID
- Venue
- Cell stem cell
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 9
- Issue
- 3
- Pages
- 233-246
- ISSN
- 1875-9777 (ISSN-L)
- 1934-5909
- OpenAlex
- W2002559578
- Cited by
- 142
- References
- 64
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 5 · 2023: 10 · 2022: 12 · 2021: 4 · 2020: 9 · 2019: 6 · 2018: 9 · 2017: 9 · 2016: 13 · 2015: 13 · 2014: 15 · 2013: 15 · 2012: 13
- FWCI
- 5.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 721 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell stem cell (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Urology › Hair Growth and Disorders
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- CBX4, human epidermal stem cells, stem cell proliferation, cellular senescence, PRC1, stem cell differentiation, epidermal homeostasis, stem cell quiescence, EZH2, DNMT1, BMI1, chromatin occupancy, transcriptome regulation
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, DNA (Cytosine-5-)-Methyltransferase 1, Adult, Cell Differentiation, Cells, Cultured, DNA (Cytosine-5-)-Methyltransferases, DNA-Binding Proteins, Epidermis, Humans, Infant, Newborn, Ligases, Male, Nuclear Proteins, Proto-Oncogene Proteins, Repressor Proteins, Transcription Factors, Keratinocytes, Mutagenesis, Site-Directed, Cellular Senescence, Gene Expression Profiling, SUMO-1 Protein, RNA, Small Interfering, Chromatin Assembly and Disassembly, Ubiquitin-Protein Ligases, Cell Proliferation, Foreskin, Adult Stem Cells, Polycomb-Group Proteins, Polycomb Repressive Complex 1, Polycomb Repressive Complex 2
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