Abstract
Pancreatic α cell senses amino acid availability to adjust secretion function and proliferation, yet the underlying molecular mechanisms remain unclear. Here, α cell-specific deletion of CBP/p300 in mice leads to hypoglucagonemia and hyperaminoacidemia, along with decreased functional pancreatic α cell mass due to impaired cell proliferation, dedifferentiation, and cell loss. The knockout of CBP/p300 blocks glucagon receptor antibody-stimulated α cell proliferation and mTORC1 signaling in mice. In CBP/p300-deficient α cells, single-cell RNA sequencing reveals upregulated autophagy-related genes and downregulated α cell identity genes and amino acid transporters, including Slc7a2. Slc7a2 is involved in regulating α cell identity gene expression through lysine-facilitated H3K27 acetylation. In addition, Slc7a2 downregulation compromises arginine-stimulated mTORC1 signaling, thereby suppressing α cell proliferation and triggering autophagy. Collectively, our findings uncover CBP/p300 as central regulators of functional α cell mass partially by orchestrating Slc7a2-mediated amino acid sensing.
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The Crebbpflox/flox and Ep300flox/flox mice are available upon request. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact. The islets Single-cell RNA sequencing data have been deposited in the GEO database under the accession codes (GSE324884). All data generated in this study are included in the main text or Supplementary Information. Source data are provided with this paper.
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Acknowledgements
This work was funded by Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0531600 and 2024ZD0531604), the National Natural Science Foundation of China (82370798, 82270860, and 82300896), and Shanghai Science and Technology Committee (23YF1437600). We thank Dr. Hai Yan (REMD Biotherapeutics, Camarillo, CA) for providing GCGR antibody.
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S.W. conceived and designed the work, performed the experiments, analyzed the data, and wrote the manuscript; T.L. and C.S. obtained and analyzed the data and revised the manuscript; J.T., X.M., Y.Y., and Y.L. conducted partial experiments; R.W. critically contributed to the discussion. F.Z., L.Z., and X.W. supervised this study and revised the manuscript. All authors read and approved the final paper.
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Wang, S., Li, T., Sheng, C. et al. CBP/p300 is critical for the expansion and maintenance of functional pancreatic α cell mass. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71499-5
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DOI: https://doi.org/10.1038/s41467-026-71499-5
