An epigenetic memory of inflammation controls context-dependent lineage plasticity in the pancreas [bulk RNA-seq]

Inflammation is essential to the disruption of tissue homeostasis, and, in the pancreas, can destabilize the identity of terminally differentiated acinar cells. Herein we employ lineage-traced mouse models to delineate the chromatin dynamics that accompany the cycle of metaplasia and regeneration following pancreatitis, and unveil the presence of an epigenetic memory of inflammation in the pancreatic acinar cell compartment. We observe that despite histologic resolution of pancreatitis, acinar cells fail to return to their molecular baseline after several months, representing an incomplete cell fate decision. In vivo, this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second inflammatory insult but increased tumorigenesis with an oncogenic Kras mutation. We demonstrate that both persistent chromatin and transcriptional changes constituting memory are recalled with oncogenic stress. Together, our findings define the dynamics and recall of an epigenetic memory of inflammation that impacts cell fate decisions in a context-dependent manner. Overall design: Characterization of bulk gene expression via RNA-seq of lineage-traced acinar and acinar-derived cells from either KrasG12D or KrasWT mice treated with caerulein (or saline as control) following 2 days, 3 weeks, or 12 weeks of recovery, with or without delayed activation of TdTomato +/- KrasG12D expression via tamoxifen administratio, as indicated