Loss of RE-1 silencing transcription factor accelerates exocrine damage from pancreatic injury

Julie K Bray,Jinmai Jiang,Mohamed Badawi,Lais S Wright,Dhruvitkumar S Sutaria,Madeline G Borcyk,Thomas D Schmittgen,Martha L Campbell-Thompson,Kristianna M Fredenburg,Ola A Elgamal,Xiuli Liu

doi:10.1038/s41419-020-2269-7

Julie K Bray, Jinmai Jiang + Show 9 more

Open Access

https://doi.org/10.1038/s41419-020-2269-7

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Abstract

Regulation of pancreas plasticity is critical for preventing injury and promoting regeneration upon tissue damage. The intricate process of pancreatic differentiation is governed by an orchestrated network of positive and negative transcription factors for appropriate gene expression. While the transcriptional repressor REST is well characterized as a silencer of neuronal genes in non-neuronal cells, the role of REST in regulating exocrine pancreas cell identity remains largely unexplored. Rest expression is increased upon injury in the mouse pancreas, such as induced acute and chronic pancreatitis and ductal adenocarcinoma. At the cellular level, Rest expression is lower in mature acinar cells compared with pancreas progenitor and ductal cells. To investigate the role of REST activity in pancreatic transdifferentiation and homeostasis, we developed a novel mouse model (Cre/RESTfl/fl) with conditional knockout (KO) of Rest expression within pancreas cells. The high Cre-mediated excision efficiency of Rest exon two KO caused decreased Rest expression and activity within the pancreas. Short-term organoid cultures of pancreatic acini to undergo acinar-to-ductal metaplasia (ADM) showed that loss of REST impedes induced ADM, while overexpression of REST increases ADM. Interestingly, REST ablation accelerated acute pancreatitis in mice treated with the cholecystokinin analog caerulein, as indicated by cellular morphology, elevated serum amylase levels and pancreatic edema. Furthermore, Cre/RESTfl/fl mice were more sensitive to acute pancreatitis injury and displayed augmented tissue damage and cellular lesions. These results suggest REST has a novel protective role against pancreatic tissue damage by acting as a regulator of exocrine cell identity.

Highlights

Pancreas functions are vital for the proper digestion of food and regulation of blood glucose levels
Digestive enzymes and bicarbonate are produced from the exocrine cells, and hormones are produced from the islet neuroendocrine cells
To investigate the role of RE-1 silencing transcription factor (REST) in the exocrine pancreas, Gene set enrichment analysis (GSEA) was performed on the gene expression profiles of normal human pancreas and pancreatic ductal adenocarcinoma tissues as described in the “Materials and methods” section

Summary

Introduction

Pancreas functions are vital for the proper digestion of food and regulation of blood glucose levels. One master regulator of directing progenitor maturation is the RE-1 silencing transcription factor (REST)[7]. REST, known as neuron restrictive silencing factor (NRSF), Official journal of the Cell Death Differentiation Association. Bray et al Cell Death and Disease (2020)11:138 has been most characterized as a seminal negative regulator that represses transcription of neuronal-related genes[8]. The appropriate downregulation of REST orchestrates neuronal differentiation that is required for neurogenesis[10,11] and includes pancreatic neuroendocrine differentiation[12,13,14]. Known REST targets encompass a variety of genes involved in synaptic formation, cellular trafficking, ion channels, cytoskeletal components, neurotransmitter receptors, and more[15,16]. Up to 90% of REST target genes are tissue and cell-type specific[20,21]

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