Multi-omic single nuclei profiling of murine pancreas shows dynamic epigenetic heterogeneity of acinar cells

The pancreatic tissue is composite and plastic. The epigenetic makeup of different cell types is poorly characterized due to the lack of protocols that enable efficient recovery of epithelial cells. Here, we improve the canonical pipeline for single-cell analysis, optimizing the harvesting of nuclei from hard-to-dissociate tissues. We provide an in-depth mapping of the murine pancreas through paired RNA/ATAC multiomic single-nucleus sequencing, documenting the transcriptomic and chromatin accessibility profiles of every cell in the parenchyma. This enables a superior examination of the exocrine fraction of the pancreas. We described endocrine-exocrine interaction in silico and validated pro-proliferative signals in vitro. At the same time, we assessed pancreatic cellular heterogeneity in a holistic manner. We showed that pancreatic acinar cells can acquire multiple phenotypic states that lead to the functional diversification of pancreatic acini. In particular, we identified ultra-specialized ZG16^HIGH cells in vivo and associated them with superior protein synthesis by tracking the incorporation of a synthetic amino acid. Leveraging the pairing of gene expression and chromatin opening, we studied the epigenetic elements that dictate acinar cell specialization and how they are affected by tissue repair after inflammation. We found that a subset of acinar cells shows enhanced sensitivity to inflammatory cues that determine extensive and persistent chromatin opening. The dataset is an open-source framework to interrogate the molecular histology of the murine pancreas.