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| Item Type: | Preprint |
|---|---|
| Title: | Pre-existing chromatin accessibility primes δ-cells for injury-induced endocrine plasticity |
| Creators Name: | Gräßlin, Jo, Chawla, Prateek, Subramanian, Padmapriya, Rajendran, Anuradha, Walda, Emilie Ida Christine, Froschauer, Alexander, Ninov, Nikolay and Junker, Jan Philipp |
| Abstract: | Adult zebrafish rapidly recover glucose homeostasis after β-cell loss, but the cellular basis and regulatory mechanisms that enable this response remain unclear. Here we combine single-cell transcriptomics, single-cell chromatin accessibility profiling, paired multiome analysis and functional perturbation to define early pancreatic recovery after β-cell ablation. We show that, during the first month after injury, insulin production is restored predominantly by sst1.1+ δ 1-cells rather than by rapid reconstitution of canonical β-cells. Following ablation, δ 1-cells adopt a bihormonal hybrid state and induce metabolic, secretory and β-cell-associated gene programs. Systematic comparison of chromatin accessibility across endocrine cell types reveals that these δ 1-cells are uniquely close to β-cells and exhibit open chromatin at β-cell enhancers in the steady state. Moreover, hybrid-cell formation occurs without major chromatin remodeling, with β-cell associated loci being already accessible in δ 1-cells before β-cell injury. A comparable permissive state is present in medaka but not in human δ-cells, suggesting that restricted insulin accessibility may represent a barrier to endocrine plasticity in the human pancreas. In zebrafish, δ 1-cells also show evidence of metabolic remodeling after β-cell loss, including rapid accumulation of neutral lipids. Finally, gene regulatory network analysis and perturbation identify meis1a/b as required regulators of δ 1 hybrid-cell formation after β-cell loss. Together, our results define pre-existing chromatin accessibility, metabolic remodeling and instructive transcriptional regulation as key features of early functional recovery after β-cell loss in the adult zebrafish pancreas. |
| Keywords: | Animals, Fish, Zebrafish |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2026.05.24.727280 |
| Date: | 27 May 2026 |
| Official Publication: | https://doi.org/10.64898/2026.05.24.727280 |
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