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| Home > Institute Collections > W500 > Senescence of human pancreatic beta cells enhances functional maturation through chromatin reorganization and promotes interferon responsiveness. |
| Home > Institute Collections > W500 > Senescence of human pancreatic beta cells enhances functional maturation through chromatin reorganization and promotes interferon responsiveness. |
| Journal Article | DKFZ-2025-02685 |
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2024
Oxford Univ. Press
Oxford
Abstract: Senescent cells can influence the function of tissues in which they reside, and their propensity for disease. A portion of adult human pancreatic beta cells express the senescence marker p16, yet it is unclear whether they are in a senescent state, and how this affects insulin secretion. We analyzed single-cell transcriptome datasets of adult human beta cells, and found that p16-positive cells express senescence gene signatures, as well as elevated levels of beta-cell maturation genes, consistent with enhanced functionality. Senescent human beta-like cells in culture undergo chromatin reorganization that leads to activation of enhancers regulating functional maturation genes and acquisition of glucose-stimulated insulin secretion capacity. Strikingly, Interferon-stimulated genes are elevated in senescent human beta cells, but genes encoding senescence-associated secretory phenotype (SASP) cytokines are not. Senescent beta cells in culture and in human tissue show elevated levels of cytoplasmic DNA, contributing to their increased interferon responsiveness. Human beta-cell senescence thus involves chromatin-driven upregulation of a functional-maturation program, and increased responsiveness of interferon-stimulated genes, changes that could increase both insulin secretion and immune reactivity.
Keyword(s): Humans (MeSH) ; Insulin-Secreting Cells: metabolism (MeSH) ; Cellular Senescence: genetics (MeSH) ; Chromatin Assembly and Disassembly (MeSH) ; Interferons: metabolism (MeSH) ; Interferons: genetics (MeSH) ; Insulin Secretion (MeSH) ; Insulin: metabolism (MeSH) ; Chromatin: metabolism (MeSH) ; Cyclin-Dependent Kinase Inhibitor p16: metabolism (MeSH) ; Cyclin-Dependent Kinase Inhibitor p16: genetics (MeSH) ; Cells, Cultured (MeSH) ; Senescence-Associated Secretory Phenotype: genetics (MeSH) ; Transcriptome (MeSH) ; Single-Cell Analysis (MeSH) ; Interferons ; Insulin ; Chromatin ; Cyclin-Dependent Kinase Inhibitor p16
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