Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity
Context-Dependent Epigenetic Regulation of Nuclear Factor of Activated T Cells 1 in Pancreatic Plasticity
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胰腺可塑性中活化 T 细胞核因子 1 的上下文相关表观遗传调控
DOI：
10.1053/j.gastro.2017.01.043
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发表时间：
2017-05-01
期刊：
影响因子：
29.4
通讯作者：
Hessmann, Elisabeth
中科院分区：
文献类型：
--
作者：
Chen, Nai-Ming;Neesse, Albrecht;Hessmann, Elisabeth
背景与目的：胰腺外分泌细胞改变细胞表型的能力是损伤后组织再生所需的，但也有助于其恶性转化和肿瘤进展。我们研究了环境依赖性信号和转录机制，决定胰腺细胞的命运决定再生和恶性。特别是，我们研究了炎症转录因子活化T细胞核因子1（NFATC1）在胰腺细胞可塑性和组织适应中的功能和调节。方法：我们分析了胰腺再生和转化过程中的细胞可塑性与胰腺特异性表达的组成型活性形式的NFATC1，或zeste增强子2同源物2（EZH2）的耗竭，在野生型或组成型激活Kras的情况下，分别在小鼠。腹腔注射雨蛙肽诱发急性和慢性胰腺炎。通过免疫组化、免疫印迹和定量逆转录聚合酶链反应研究了小鼠人胰腺组织和细胞中NFATC1表达的EZH2依赖性调节。我们使用EZH2和NFATC1抑制的遗传学和药理学方法来研究通路中断对胰腺形态和功能的后果。通过染色质免疫沉淀试验研究了NFATC1基因的表观遗传修饰。研究结果：在人类样本和小鼠中，NFATC1在对腺泡细胞损伤的早期适应中被快速且瞬时地诱导，其中其促进腺泡细胞转分化并阻断化生胰腺细胞的增殖。然而，在再生的后期阶段，Nfatc1通过EZH2依赖性组蛋白甲基化在表观遗传学上沉默，以使腺泡细胞重新分化并防止器官萎缩和外分泌不足。相反，胰腺导管腺癌细胞中KRAS信号的致癌激活逆转了EZH2对NFATC1基因的依赖性作用，并且是EZH2介导的NFATC1转录激活所必需的。结论：在人类和小鼠胰腺细胞和组织的研究中，我们确定了NFATc1活性的背景特异性表观遗传调节是胰腺细胞可塑性的重要机制。因此，EZH2抑制剂可能干扰NFATC1的致癌活性，并用于治疗胰腺导管腺癌。
BACKGROUND & AIMS: The ability of exocrine pancreatic cells to change the cellular phenotype is required for tissue regeneration upon injury, but also contributes to their malignant transformation and tumor progression. We investigated context-dependent signaling and transcription mechanisms that determine pancreatic cell fate decisions toward regeneration and malignancy. In particular, we studied the function and regulation of the inflammatory transcription factor nuclear factor of activated T cells 1 (NFATC1) in pancreatic cell plasticity and tissue adaptation. METHODS: We analyzed cell plasticity during pancreatic regeneration and transformation in mice with pancreas-specific expression of a constitutively active form of NFATC1, or depletion of enhancer of zeste 2 homologue 2 (EZH2), in the context of wild-type or constitutively activate Kras, respectively. Acute and chronic pancreatitis were induced by intraperitoneal injection of caerulein. EZH2-dependent regulation of NFATC1 expression was studied in mouse in human pancreatic tissue and cells by immunohistochemistry, immunoblotting, and quantitative reverse transcription polymerase chain reaction. We used genetic and pharmacologic approaches of EZH2 and NFATC1 inhibition to study the consequences of pathway disruption on pancreatic morphology and function. Epigenetic modifications on the NFATC1 gene were investigated by chromatin immunoprecipitation assays. RESULTS: NFATC1 was rapidly and transiently induced in early adaptation to acinar cell injury in human samples and in mice, where it promoted acinar cell trans-differentiation and blocked proliferation of metaplastic pancreatic cells. However, in late stages of regeneration, Nfatc1 was epigenetically silenced by EZH2-dependent histone methylation, to enable acinar cell redifferentiation and prevent organ atrophy and exocrine insufficiency. In contrast, oncogenic activation of KRAS signaling in pancreatic ductal adenocarcinoma cells reversed the EZH2-dependent effects on the NFATC1 gene and was required for EZH2-mediated transcriptional activation of NFATC1. CONCLUSIONS: In studies of human and mouse pancreatic cells and tissue, we identified context-specific epigenetic regulation of NFATc1 activity as an important mechanism of pancreatic cell plasticity. Inhibitors of EZH2 might therefore interfere with oncogenic activity of NFATC1 and be used in treatment of pancreatic ductal adenocarcinoma.