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bioRxiv · 10.64898/2026.05.24.727280

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

Graesslin, J.·Chawla, P.·Subramanian, P.·Rajendran, A.·Walda, E. I. C.·Froschauer, A.·Ninov, N.·Junker, J. P.
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Abstract

Adult zebrafish rapidly recover glucose homeostasis after {beta}-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 {beta}-cell ablation. We show that, during the first month after injury, insulin production is restored predominantly by sst1.1+ {delta}1-cells rather than by rapid reconstitution of canonical {beta}-cells. Following ablation, {delta}1-cells adopt a bihormonal hybrid state and induce metabolic, secretory and {beta}-cell-associated gene programs. Systematic comparison of chromatin accessibility across endocrine cell types reveals that these {delta}1-cells are uniquely close to {beta}-cells and exhibit open chromatin at {beta}-cell enhancers in the steady state. Moreover, hybrid-cell formation occurs without major chromatin remodeling, with {beta}-cell associated loci being already accessible in {delta}1-cells before {beta}-cell injury. A comparable permissive state is present in medaka but not in human {delta}-cells, suggesting that restricted insulin accessibility may represent a barrier to endocrine plasticity in the human pancreas. In zebrafish, {delta}1-cells also show evidence of metabolic remodeling after {beta}-cell loss, including rapid accumulation of neutral lipids. Gene regulatory network analysis and perturbation identify meis1a/b as required regulators of {delta}1 hybrid-cell formation after {beta}-cell loss in zebrafish, whereas meis1a/b are not upregulated following {beta}-cell ablation in medaka. Together, our results define pre-existing chromatin accessibility, metabolic remodeling and instructive transcriptional regulation as key features of early functional recovery after {beta}-cell loss in the adult zebrafish pancreas.

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Graesslin, J., Chawla, P., Subramanian, P., Rajendran, A., Walda, E. I. C., Froschauer, A., Ninov, N., Junker, J. P.. 2026-05-27. Pre-existing chromatin accessibility primes δ-cells for injury-induced endocrine plasticity. https://doi.org/10.64898/2026.05.24.727280

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