Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas

Isidoro Cobo, Paola Martinelli, Marta Flández, Latifa Bakiri, Mingfeng Zhang, Enrique Carrillo-De-Santa-Pau, Jinping Jia, Víctor J.Sánchez Arévalo Lobo, Diego Megías, Irene Felipe, Natalia Del Pozo, Irene Millán, Liv Thommesen, Torunn Bruland, Sara H. Olson, Jill Smith, Kristina Schoonjans, William R. Bamlet, Gloria M Petersen, Núria MalatsLaufey T. Amundadottir, Erwin F. Wagner, Francisco X. Real

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)533-537
Number of pages5
JournalNature
Volume554
Issue number7693
DOIs
StatePublished - Feb 22 2018

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Pancreas
Inflammation
Gene Regulatory Networks
Orphan Nuclear Receptors
Genes
Endoplasmic Reticulum Stress
Genome-Wide Association Study
Transcription Factor AP-1
Pancreatitis
Glucocorticoids
Single Nucleotide Polymorphism
Regeneration
Cell Differentiation
Neoplasms
Adenocarcinoma
Epithelial Cells
Cholesterol
Phenotype
Glucose
Messenger RNA

ASJC Scopus subject areas

  • General

Cite this

Cobo, I., Martinelli, P., Flández, M., Bakiri, L., Zhang, M., Carrillo-De-Santa-Pau, E., ... Real, F. X. (2018). Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature, 554(7693), 533-537. https://doi.org/10.1038/nature25751

Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. / Cobo, Isidoro; Martinelli, Paola; Flández, Marta; Bakiri, Latifa; Zhang, Mingfeng; Carrillo-De-Santa-Pau, Enrique; Jia, Jinping; Lobo, Víctor J.Sánchez Arévalo; Megías, Diego; Felipe, Irene; Del Pozo, Natalia; Millán, Irene; Thommesen, Liv; Bruland, Torunn; Olson, Sara H.; Smith, Jill; Schoonjans, Kristina; Bamlet, William R.; Petersen, Gloria M; Malats, Núria; Amundadottir, Laufey T.; Wagner, Erwin F.; Real, Francisco X.

In: Nature, Vol. 554, No. 7693, 22.02.2018, p. 533-537.

Research output: Contribution to journalArticle

Cobo, I, Martinelli, P, Flández, M, Bakiri, L, Zhang, M, Carrillo-De-Santa-Pau, E, Jia, J, Lobo, VJSA, Megías, D, Felipe, I, Del Pozo, N, Millán, I, Thommesen, L, Bruland, T, Olson, SH, Smith, J, Schoonjans, K, Bamlet, WR, Petersen, GM, Malats, N, Amundadottir, LT, Wagner, EF & Real, FX 2018, 'Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas', Nature, vol. 554, no. 7693, pp. 533-537. https://doi.org/10.1038/nature25751
Cobo I, Martinelli P, Flández M, Bakiri L, Zhang M, Carrillo-De-Santa-Pau E et al. Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature. 2018 Feb 22;554(7693):533-537. https://doi.org/10.1038/nature25751
Cobo, Isidoro ; Martinelli, Paola ; Flández, Marta ; Bakiri, Latifa ; Zhang, Mingfeng ; Carrillo-De-Santa-Pau, Enrique ; Jia, Jinping ; Lobo, Víctor J.Sánchez Arévalo ; Megías, Diego ; Felipe, Irene ; Del Pozo, Natalia ; Millán, Irene ; Thommesen, Liv ; Bruland, Torunn ; Olson, Sara H. ; Smith, Jill ; Schoonjans, Kristina ; Bamlet, William R. ; Petersen, Gloria M ; Malats, Núria ; Amundadottir, Laufey T. ; Wagner, Erwin F. ; Real, Francisco X. / Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. In: Nature. 2018 ; Vol. 554, No. 7693. pp. 533-537.
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AU - Cobo, Isidoro

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AU - Carrillo-De-Santa-Pau, Enrique

AU - Jia, Jinping

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AU - Schoonjans, Kristina

AU - Bamlet, William R.

AU - Petersen, Gloria M

AU - Malats, Núria

AU - Amundadottir, Laufey T.

AU - Wagner, Erwin F.

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