Senescence of human pancreatic beta cells enhances functional maturation through chromatin reorganization and promotes interferon responsiveness

Milan Patra, Agnes Klochendler, Reba Condiotti, Binyamin Kaffe, Sharona Elgavish, Zeina Drawshy, Dana Avrahami, Masashi Narita, Matan Hofree, Yotam Drier, Eran Meshorer, Yuval Dor, Ittai Ben-Porath*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)6298-6316
Number of pages19
JournalNucleic Acids Research
Volume52
Issue number11
DOIs
StatePublished - 24 Jun 2024

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© The Author(s) 2024.

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