Regeneration from acute pancreatitis requires transcriptional silencing of NFATc1
Introduction: Tissue injury initiates a complex regenerative programme ensuring complete restoration of organ structure and function. Understanding the molecular key events in mediation and regeneration from pancreas injury is critical to develop novel therapeutic strategies. Recent evidence suggests important roles for developmental and inflammatory transcription factors in several steps of the regeneration process.
Aims: To analyze whether and how the inflammatory transcription factor NFATc1 is involved in the course of acute pancreatitis.
Methods: Caerulein and L-Arginin were used to induce acute pancreatitis in different pancreas specific transgenic mice models with differential expression of NFATc1. Mice were sacrificed at different time points after induction of acute pancreatitis to isolate pancreata for further analysis. Gene expression in mice tissue and acinar cell explants were determined by using RT-PCR, immunoblotting, immunofluorescence and immunohistochemical stainings. Local histone modifications on the NFATc1 promoter were investigated by ChIP analysis.
Results: Caerulein mediated acute pancreatitis initiates acinar to ductal metaplasia, which goes along with activation of NFATc1 in metaplastic areas of the pancreas. Regeneration of the pancreas requires inactivation of NFATc1 by H3K27 trimethylation mediated by the Polycomb protein EZH2. While pharmacological or genetic inactivation of NFATc1 in mice accelerates pancreas regeneration, sustained activation of NFATc1 overcomes transcriptional silencing and fully prevents restoration of the organ.
Conclusion: Our results provide evidence, that transcriptional silencing of NFATc1 by EZH2 is an inevitable prerequisite for sufficient regeneration from acute pancreatitis.