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Abstract：
UNASSIGNED: Increased expression of IFN-stimulated gene 15 (ISG15) and subsequently increased ISGylation are key factors in the host response to viral infection. In this study, we sought to characterize the expression of ISG15, ISGylation, and associated enzymes at each stage of differentiation from induced pluripotent stem cells (iPSCs) to hepatocytes.
UNASSIGNED: To study the regulation of ISGylation, we utilized patient samples and in vitro cell culture models including iPSCs, hepatocytes-like cells, immortalized cell lines, and primary human hepatocytes. Protein/mRNA expression were measured following treatment with poly(I:C), IFNα and HCV infection.
UNASSIGNED: When compared to HLCs, we observed several novel aspects of the ISGylation pathway in iPSCs. These include a lower baseline expression of the ISGylation-activating enzyme, UBE1L, a lack of IFN-induced expression of the ISGylation-conjugation enzyme UBE2L6, an attenuated activation of the transcription factor STAT1 and constitutive expression of SOCS1. ISGylation was observed in iPSCs following downregulation of SOCS1, which facilitated STAT1 activation and subsequently increased expression of UBE2L6. Intriguingly, HCV permissive transformed hepatoma cell lines demonstrated higher intrinsic expression of SOCS1 and weaker ISGylation following IFN treatment. SOCS1 downregulation in HCV-infected Huh 7.5.1 cells led to increased ISGylation.
UNASSIGNED: Herein, we show that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Furthermore, as iPSCs differentiate into hepatocytes, epigenetic mechanisms regulate ISGylation by modifying UBE1L and SOCS1 expression levels. Overall, this study demonstrates that the development of cell-intrinsic innate immunity during the differentiation of iPSCs to hepatocytes provides insight into cell type-specific regulation of host defense responses and related oncogenic processes.
UNASSIGNED: To elucidate the mechanism underlying regulation of ISGylation, a key process in the innate immune response, we studied changes in ISGylation-associated genes at the different stages of differentiation from iPSCs to hepatocytes. We found that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Importantly, epigenetic regulation of SOCS1 and subsequently ISGylation may be important factors in the development of cell type-specific host defense responses in hepatocytes that should be considered when studying chronic infections and oncogenic processes in the liver.
UNASSIGNED: To study the regulation of ISGylation, we utilized patient samples and in vitro cell culture models including iPSCs, hepatocytes-like cells, immortalized cell lines, and primary human hepatocytes. Protein/mRNA expression were measured following treatment with poly(I:C), IFNα and HCV infection.
UNASSIGNED: When compared to HLCs, we observed several novel aspects of the ISGylation pathway in iPSCs. These include a lower baseline expression of the ISGylation-activating enzyme, UBE1L, a lack of IFN-induced expression of the ISGylation-conjugation enzyme UBE2L6, an attenuated activation of the transcription factor STAT1 and constitutive expression of SOCS1. ISGylation was observed in iPSCs following downregulation of SOCS1, which facilitated STAT1 activation and subsequently increased expression of UBE2L6. Intriguingly, HCV permissive transformed hepatoma cell lines demonstrated higher intrinsic expression of SOCS1 and weaker ISGylation following IFN treatment. SOCS1 downregulation in HCV-infected Huh 7.5.1 cells led to increased ISGylation.
UNASSIGNED: Herein, we show that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Furthermore, as iPSCs differentiate into hepatocytes, epigenetic mechanisms regulate ISGylation by modifying UBE1L and SOCS1 expression levels. Overall, this study demonstrates that the development of cell-intrinsic innate immunity during the differentiation of iPSCs to hepatocytes provides insight into cell type-specific regulation of host defense responses and related oncogenic processes.
UNASSIGNED: To elucidate the mechanism underlying regulation of ISGylation, a key process in the innate immune response, we studied changes in ISGylation-associated genes at the different stages of differentiation from iPSCs to hepatocytes. We found that high basal levels of SOCS1 inhibit STAT1 activation and subsequently IFN-induced UBE2L6 and ISGylation in iPSCs. Importantly, epigenetic regulation of SOCS1 and subsequently ISGylation may be important factors in the development of cell type-specific host defense responses in hepatocytes that should be considered when studying chronic infections and oncogenic processes in the liver.
摘要：
未经证实：IFN刺激的基因15（ISG15）的表达增加以及随后的ISG化增加是宿主对病毒感染反应的关键因素。在这项研究中,我们试图表征ISG15的表达，ISGylation，以及从诱导多能干细胞（iPSC）分化为肝细胞的每个阶段的相关酶。
UNASSIGNED：为了研究ISG化的调节，我们利用患者样本和体外细胞培养模型，包括iPSCs，肝细胞样细胞，永生化细胞系，和原代人肝细胞。在用聚(I:C)处理后测量蛋白质/mRNA表达,IFNα和HCV感染。
未经评估：与HLC相比，我们观察到iPSCs中ISGylation途径的几个新方面。这些包括ISG化激活酶的较低基线表达，UBE1L,缺乏IFN诱导的ISGylation缀合酶UBE2L6的表达，转录因子STAT1的激活减弱和SOCS1的组成型表达。在下调SOCS1后，在iPSC中观察到ISG化，这促进了STAT1激活并随后增加了UBE2L6的表达。有趣的是，HCV允许转化的肝癌细胞系在IFN治疗后表现出较高的SOCS1内在表达和较弱的ISG化。HCV感染的Huh7.5.1细胞中的SOCS1下调导致ISG化增加。
未经批准：此处，我们表明，高基础水平的SOCS1抑制STAT1激活，随后抑制IFN诱导的iPSCs中的UBE2L6和ISG化。此外，随着iPSCs分化为肝细胞，表观遗传机制通过修饰UBE1L和SOCS1表达水平来调节ISG化。总的来说,这项研究表明，在iPSCs分化为肝细胞的过程中，细胞固有先天免疫的发展提供了对宿主防御反应和相关致癌过程的细胞类型特异性调节的见解。
未经授权：为了阐明ISG化的潜在调节机制，先天免疫反应的一个关键过程，我们研究了从iPSCs分化为肝细胞的不同阶段ISG相关基因的变化.我们发现，高基础水平的SOCS1抑制STAT1激活，随后在iPSC中IFN诱导的UBE2L6和ISG化。重要的是,SOCS1的表观遗传调控和随后的ISG化可能是肝细胞中细胞类型特异性宿主防御反应发展的重要因素，在研究肝脏中的慢性感染和致癌过程时应考虑这些因素。
UNASSIGNED：为了研究ISG化的调节，我们利用患者样本和体外细胞培养模型，包括iPSCs，肝细胞样细胞，永生化细胞系，和原代人肝细胞。在用聚(I:C)处理后测量蛋白质/mRNA表达,IFNα和HCV感染。
未经评估：与HLC相比，我们观察到iPSCs中ISGylation途径的几个新方面。这些包括ISG化激活酶的较低基线表达，UBE1L,缺乏IFN诱导的ISGylation缀合酶UBE2L6的表达，转录因子STAT1的激活减弱和SOCS1的组成型表达。在下调SOCS1后，在iPSC中观察到ISG化，这促进了STAT1激活并随后增加了UBE2L6的表达。有趣的是，HCV允许转化的肝癌细胞系在IFN治疗后表现出较高的SOCS1内在表达和较弱的ISG化。HCV感染的Huh7.5.1细胞中的SOCS1下调导致ISG化增加。
未经批准：此处，我们表明，高基础水平的SOCS1抑制STAT1激活，随后抑制IFN诱导的iPSCs中的UBE2L6和ISG化。此外，随着iPSCs分化为肝细胞，表观遗传机制通过修饰UBE1L和SOCS1表达水平来调节ISG化。总的来说,这项研究表明，在iPSCs分化为肝细胞的过程中，细胞固有先天免疫的发展提供了对宿主防御反应和相关致癌过程的细胞类型特异性调节的见解。
未经授权：为了阐明ISG化的潜在调节机制，先天免疫反应的一个关键过程，我们研究了从iPSCs分化为肝细胞的不同阶段ISG相关基因的变化.我们发现，高基础水平的SOCS1抑制STAT1激活，随后在iPSC中IFN诱导的UBE2L6和ISG化。重要的是,SOCS1的表观遗传调控和随后的ISG化可能是肝细胞中细胞类型特异性宿主防御反应发展的重要因素，在研究肝脏中的慢性感染和致癌过程时应考虑这些因素。
