TY - JOUR
T1 - Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas
AU - Cobo, Isidoro
AU - Martinelli, Paola
AU - Flández, Marta
AU - Bakiri, Latifa
AU - Zhang, Mingfeng
AU - Carrillo-De-Santa-Pau, Enrique
AU - Jia, Jinping
AU - Lobo, Víctor J.Sánchez Arévalo
AU - Megías, Diego
AU - Felipe, Irene
AU - Del Pozo, Natalia
AU - Millán, Irene
AU - Thommesen, Liv
AU - Bruland, Torunn
AU - Olson, Sara H.
AU - Smith, Jill
AU - Schoonjans, Kristina
AU - Bamlet, William R.
AU - Petersen, Gloria M.
AU - Malats, Núria
AU - Amundadottir, Laufey T.
AU - Wagner, Erwin F.
AU - Real, Francisco X.
N1 - Publisher Copyright:
© 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2018/2/22
Y1 - 2018/2/22
N2 - Chronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, including cholesterol and glucose metabolism in the liver, resolution of endoplasmic reticulum stress, intestinal glucocorticoid production, pancreatic development and acinar differentiation. In genome-wide association studies, single nucleotide polymorphisms in the vicinity of NR5A2 have previously been associated with the risk of pancreatic adenocarcinoma. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration and cooperates with mutant Kras in tumour progression. Here, using a global transcriptomic analysis, we describe an epithelial-cell-Autonomous basal pre-inflammatory state in the pancreas of Nr5a2 +/â mice that is reminiscent of the early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreases with reduced expression of NR5A2 mRNA. In Nr5a2 +/â mice, NR5A2 undergoes a marked transcriptional switch, relocating from differentiation-specific to inflammatory genes and thereby promoting gene transcription that is dependent on the AP-1 transcription factor. Pancreatic deletion of Jun rescues the pre-inflammatory phenotype, as well as binding of NR5A2 to inflammatory gene promoters and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programmes. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.
AB - Chronic inflammation increases the risk of developing one of several types of cancer. Inflammatory responses are currently thought to be controlled by mechanisms that rely on transcriptional networks that are distinct from those involved in cell differentiation. The orphan nuclear receptor NR5A2 participates in a wide variety of processes, including cholesterol and glucose metabolism in the liver, resolution of endoplasmic reticulum stress, intestinal glucocorticoid production, pancreatic development and acinar differentiation. In genome-wide association studies, single nucleotide polymorphisms in the vicinity of NR5A2 have previously been associated with the risk of pancreatic adenocarcinoma. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration and cooperates with mutant Kras in tumour progression. Here, using a global transcriptomic analysis, we describe an epithelial-cell-Autonomous basal pre-inflammatory state in the pancreas of Nr5a2 +/â mice that is reminiscent of the early stages of pancreatitis-induced inflammation and is conserved in histologically normal human pancreases with reduced expression of NR5A2 mRNA. In Nr5a2 +/â mice, NR5A2 undergoes a marked transcriptional switch, relocating from differentiation-specific to inflammatory genes and thereby promoting gene transcription that is dependent on the AP-1 transcription factor. Pancreatic deletion of Jun rescues the pre-inflammatory phenotype, as well as binding of NR5A2 to inflammatory gene promoters and the defective regenerative response to damage. These findings support the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programmes. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.
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U2 - 10.1038/nature25751
DO - 10.1038/nature25751
M3 - Article
C2 - 29443959
AN - SCOPUS:85042466372
SN - 0028-0836
VL - 554
SP - 533
EP - 537
JO - Nature
JF - Nature
IS - 7693
ER -