- Hoang CQ, Hale MA, Azevedo-Pouly A, Elsässer HP, Deering TG, Willet SG, Pan FC, Magnuson MA, Wright CV, Swift GH, MacDonald RJ. Transcriptional Maintenance of Pancreatic Acinar Identity, Differentiation and Homeostasis by PTF1A. Molecular and cellular biology. 2016 Oct 3. PMID: 27697859 [PubMed].
Maintenance of cell-type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo. RNA-Seq and ChIP-Seq results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes; some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma.