Gene expression dynamics after murine pancreatitis unveils novel roles for Hnf1α in acinar cell homeostasis

Molero, Xavier; Vaquero, Eva C.; Flández, Marta; González, Ana María; Ortiz, M; Cibrián–Uhalte, Elena; Servitja, Joan Marc; Merlos, Anna; Juanpere, Núria; Massumi, Mohammad; Skoudy, Anouchka; MacDonald, Raymond J.; Ferrer, Jorge; Real, Francisco X.

doi:10.1136/gutjnl-2011-300360

Cited by 44 publications

(46 citation statements)

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“…In addition, HNF4A and FOXA2 are predicted to target the HNF1A promoter as well. Remarkably, all these predictions are supported by independent experimental evidence (Piaggio et al 1994;Boj et al 2001;Bartoov-Shifman et al 2002;Tomaru et al 2009;Bochkis et al 2012;Molero et al 2012).…”

Section: Overview Of the Analyses Performed By Ismaramentioning

confidence: 70%

ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs

et al. 2014

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Accurate reconstruction of the regulatory networks that control gene expression is one of the key current challenges in molecular biology. Although gene expression and chromatin state dynamics are ultimately encoded by constellations of binding sites recognized by regulators such as transcriptions factors (TFs) and microRNAs (miRNAs), our understanding of this regulatory code and its context-dependent read-out remains very limited. Given that there are thousands of potential regulators in mammals, it is not practical to use direct experimentation to identify which of these play a key role for a particular system of interest. We developed a methodology that models gene expression or chromatin modifications in terms of genome-wide predictions of regulatory sites and completely automated it into a web-based tool called ISMARA (Integrated System for Motif Activity Response Analysis). Given only gene expression or chromatin state data across a set of samples as input, ISMARA identifies the key TFs and miRNAs driving expression/chromatin changes and makes detailed predictions regarding their regulatory roles. These include predicted activities of the regulators across the samples, their genome-wide targets, enriched gene categories among the targets, and direct interactions between the regulators. Applying ISMARA to data sets from well-studied systems, we show that it consistently identifies known key regulators ab initio. We also present a number of novel predictions including regulatory interactions in innate immunity, a master regulator of mucociliary differentiation, TFs consistently disregulated in cancer, and TFs that mediate specific chromatin modifications.

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Section: Overview Of the Analyses Performed By Ismaramentioning

confidence: 70%

ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs

et al. 2014

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“…Caerulein administration leads to rapid downregulation of pancreatic amylase 7. Amy2, CpA and Cel (0, 8 h and day 1) were decreased by 30%–40% in Mnk1 +/+ mice (figure 5A and online supplementary figure S7A).…”

Section: Resultsmentioning

confidence: 98%

“…Pancreatic lysates were prepared as described 7. Acini were isolated with collagenase (NB8 Broad Range, SERVA) 20.…”

Section: Methodsmentioning

confidence: 99%

“…Initial events include impaired exocytosis and intracellular activation of trypsinogen; cathepsin B has been proposed to play a crucial role in this process 5. Acute caerulein-induced pancreatic damage leads to the transient downregulation of the acinar transcription programme 6 7. Persistent stress leads to sustained suppression of acinar differentiation favouring acino-ductal metaplasia, a preneoplastic lesion in models of pancreatic ductal adenocarcinoma 8 9…”

Section: Introductionmentioning

confidence: 99%

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Mnk1 is a novel acinar cell-specific kinase required for exocrine pancreatic secretion and response to pancreatitis in mice

Cendrowski

Lobo

Sendler

et al. 2014

Gut

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“…The current notion is that the control of inflammatory responses relies on transcriptional networks distinct from those involved in cell differentiation 2,3 . The orphan nuclear receptor NR5A2 (also known as LRH-1) participates in a wide variety of processes including cholesterol and glucose metabolism in the liver, resolution of ER stress, intestinal glucocorticoid production, pancreatic development, and acinar differentiation [4][5][6][7][8] . In mice, Nr5a2 deletion leads to variable degrees of pancreatic hypoplasia depending on the timing of its inactivation 6,8 .…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

Cobo

Martinelli

Flández

et al. 2017

Preprint

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Tissue-specific differentiation and inflammatory programmes are thought to independently contribute to disease. The orphan nuclear receptor NR5A2 is a key regulator of pancreas differentiation and SNPs in or near the human gene are associated with risk of pancreatic cancer. In mice, Nr5a2 heterozygosity sensitizes the pancreas to damage, impairs regeneration, and cooperates with mutant KRas in tumor progression. Through global transcriptomic analysis, we uncover a basal preinflammatory state in the pancreas of Nr5a2 heterozygous mice that is reminiscent of pancreatitis-induced inflammation and is conserved in histologically normal human pancreata with reduced NR5A2 mRNA expression. In Nr5a2 +/-mice, Nr5a2 undergoes a dramatic transcriptional switch relocating from tissue-specific to inflammatory loci thereby promoting AP-1-dependent gene transcription. Importantly, deletion of c-Jun in the pancreas of these mice rescues the pre-inflammatory phenotype and the defective regenerative response to damage. These findings provide compelling evidence that the same transcriptional networks supporting homeostasis in normal tissue can be subverted to foster inflammation upon genetic or environmental constraints.

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Gene expression dynamics after murine pancreatitis unveils novel roles for Hnf1α in acinar cell homeostasis

Cited by 44 publications

References 50 publications

ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs

ISMARA: automated modeling of genomic signals as a democracy of regulatory motifs

Mnk1 is a novel acinar cell-specific kinase required for exocrine pancreatic secretion and response to pancreatitis in mice

Transcriptional regulation by NR5A2 couples cell differentiation and inflammation in the pancreas

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