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Mapping cellular plasticity through the lens of Fra1 during KrasG12D mediated pancreatic acinar to ductal metaplasia [CUT&RUN]

GSE235540 Mus musculus Genome binding/occupancy profiling by high throughput sequencing 6 samples Submitted 2024/06/09 Platform GPL24247
Summary
Acinar cells have been proposed as a cell-of-origin for pancreatic intraepithelial neoplasia (PanIN) after undergoing a highly regulated acinar to ductal metaplasia (ADM) process. ADM can be triggered by pancreatitis causing acinar cells de-differentiate to a ductal-like state. We identify Fra1 (gene name Fosl1) as the most enriched transcription factor during KrasG12D acute pancreatitis mediated injury. We have elucidated the functional role of Fra1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D (Ptf1aCreERT;KrasG12D;Fosl1fl/fl;YFP) . Using single nuclei ATAC-seq and bulk-RNA seq, we used pseudotime analysis and developed a gene-regulatory network governing de-differentiation to demonstrate that Fosl1 knockout mice are delayed in the onset of ADM and accompanying recovery. Fosl1 depletion prevents the pro-inflammatory effects of G-CSF, an ADM-promoting cytokine, suggesting that the G-CSF/Fra1 signaling axis can modulate ADM. Overall, our studies mark the first time a discrete transcriptional factor has been linked to the temporal regulation of ADM.
Published in
FRA1 controls acinar cell plasticity during murine Kras(G12D)-induced pancreatic acinar to ductal metaplasia
Li AL, Sugiura K, Nishiwaki N et al. · Developmental cell 2024 · PMID 39178842 · doi:10.1016/j.devcel.2024.07.021
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Also filed as BioProject PRJNA986434 and SRA study SRP445305. Searching any of these in the dataset finder brings you back here.

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