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Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas

机译：NR5A2的转录调控将胰腺的分化和炎症联系起来

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摘要

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(1-3). 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(4-8). In genome-wide association studies(9,10), 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(11). Here, using a global transcriptomic analysis, we describe an epithelial-cell- autonomous basal pre-inflammatory state in the pancreas of Nr5a2(+/-) 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(+/-) 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.
机译：慢性炎症会增加患上几种癌症之一的风险。目前认为炎症反应是由依赖转录网络的机制控制的，该转录网络不同于参与细胞分化的转录网络（1-3）。孤儿核受体NR5A2参与广泛的过程，包括肝脏中的胆固醇和葡萄糖代谢，内质网应激的缓解，肠糖皮质激素的产生，胰腺发育和腺泡分化（4-8）。在全基因组关联研究中（9,10），NR5A2附近的单核苷酸多态性以前曾与胰腺腺癌的风险有关。在小鼠中，Nr5a2杂合性可使胰腺对损伤敏感，损害再生并在肿瘤进展中与突变Kras协同作用（11）。在这里，使用全局转录组分析，我们描述了Nr5a2（+/-）小鼠胰腺中上皮细胞自主的基础炎症前状态，让人联想到胰腺炎诱发的炎症的早期，并且在组织学上正常NR5A2 mRNA表达降低的人胰脏。在Nr5a2（+/-）小鼠中，NR5A2经历了明显的转录转换，从分化特异性基因重新定位到炎症基因，从而促进了依赖于AP-1转录因子的基因转录。胰腺的Jun缺失可以挽救炎症前的表型，以及NR5A2与炎症基因启动子的结合以及对损伤的不良再生反应。这些发现支持这样的观点，即在胰腺中，参与分化特异性功能的转录网络也会抑制炎症程序。在遗传或环境限制的条件下，这些网络可以被破坏以促进炎症。

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  • 来源
    《Nature》 |2018年第7693期|533-537|共5页
  • 作者

    Cobo Isidoro; Martinelli Paola; Flandez Marta; Bakiri Latifa; Zhang Mingfeng; Carrillo-de-Santa-Pau Enrique; Jia Jinping; Sanchez-Arevalo Lobo Victor J.; Megias Diego; Felipe Irene; del Pozo Natalia; Millan Irene; Thommesen Liv; Bruland Torunn; Olson Sara H.; Smith Jill; Schoonjans Kristina; Bamlet William R.; Petersen Gloria M.; Malats Nuria; Amundadottir Laufey T.; Wagner Erwin F.; Real Francisco X.;

  • 作者单位

    Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain;

    Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain|Med Univ Vienna, Inst Canc Res, Dept Med 1, Vienna, Austria;

    Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain|Spanish Natl Cardiovasc Res Ctr CNIC, Tissue Regenerat Lab, Madrid, Spain;

    Spanish Natl Canc Res Ctr CNIO, Genes Dev & Dis Grp, Madrid, Spain;

    NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA;

    Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain;

    NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA;

    Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain|Univ Francisco Vitoria, Fac Ciencias Biosanitarias, Dept Biotechnol, Pozuelo De Alarcon, Spain;

    Spanish Natl Canc Res Ctr CNIO, Confocal Microscopy Unit, Madrid, Spain;

    Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain;

    Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain|CIBERONC, Epithelial Carcinogenesis Grp, Spanish Natl Canc Res Ctr CNIO, Madrid, Spain;

    Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain|CIBERONC, Epithelial Carcinogenesis Grp, Spanish Natl Canc Res Ctr CNIO, Madrid, Spain;

    Norwegian Univ Sci & Technol NTNU, Dept Biomed Sci, Trondheim, Norway;

    St Olavs Univ Hosp, Med Clin, Trondheim, Norway|Norwegian Univ Sci & Technol NTNU, Dept Clin & Mol Med, Trondheim, Norway;

    Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA;

    Georgetown Univ, Dept Gastroenterol, Washington, DC 20007 USA|Georgetown Univ, Dept Hepatol, Washington, DC 20007 USA;

    Ecole Polytech Fed Lausanne, Lausanne, Switzerland;

    Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA;

    Mayo Clin, Dept Hlth Sci Res, Div Epidemiol, Rochester, MN 55905 USA;

    Spanish Natl Canc Res Ctr CNIO, Genet & Mol Epidemiol Grp, Madrid, Spain|CIBERONC, Genet & Mol Epidemiol Grp, Spanish Natl Canc Res Ctr CNIO, Madrid, Spain;

    NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA;

    Spanish Natl Canc Res Ctr CNIO, Genes Dev & Dis Grp, Madrid, Spain;

    Spanish Natl Canc Res Ctr CNIO, Epithelial Carcinogenesis Grp, Madrid, Spain|CIBERONC, Epithelial Carcinogenesis Grp, Spanish Natl Canc Res Ctr CNIO, Madrid, Spain|Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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