Pre-existing chromatin accessibility primes δ-cells for injury-induced endocrine plasticity

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 ⁺ δ1-cells rather than by rapid reconstitution of canonical β-cells. Following ablation, δ1-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 δ1-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 δ1-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, δ1-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 δ1 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.