Optimized logic rules reveal interferon-γ-induced modes regulated by histone deacetylases and protein tyrosine phosphatases.
Optimized logic rules reveal interferon-γ-induced modes regulated by histone deacetylases and protein tyrosine phosphatases.
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优化的逻辑规则揭示了由组蛋白脱乙酰酶和蛋白酪氨酸磷酸酶调节的干扰素-γ诱导模式。
DOI：
10.1111/imm.12707
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发表时间：
2017
期刊：
影响因子：
6.4
通讯作者：
Thakar,Juilee
中科院分区：
文献类型：
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作者：
VanTwisk,Daniel;Murphy,ShawnP;Thakar,Juilee
促炎症细胞因子干扰素-γ(干扰素-γ)是激活针对肿瘤和细胞内病原体的天然免疫和获得性免疫的关键。干扰素-γ在孕妇和小鼠的胎儿-母体界面分泌。与母体血液接触的胎盘外层由半异基因滋养层细胞组成，构成胎儿-母体界面的胎儿成分。在胎儿-母体界面同时存在促炎性干扰素-γ和滋养层细胞似乎代表了一种免疫学悖论，因为滋养层对干扰素-γ的反应可能导致母体免疫的激活和随后的胎盘攻击。然而，我们以前的研究表明，干扰素-γ反应基因(Irg)在人和小鼠滋养层细胞中的表达是负调控的。在人细胞滋养层细胞和滋养层细胞来源的绒癌细胞中，Janus激酶信号被蛋白酪氨酸磷酸酶(PTPs)阻断，而在小鼠滋养层细胞中，组蛋白脱乙酰酶(HDAC)抑制IRG的表达。在这里，我们使用全基因组转录图谱来研究PTPs和HDAC在调节人绒毛癌细胞中IRG表达方面的共同作用。逻辑规则被优化，以得出控制PTP和HDAC抑制剂不同处理组合时观察到的基因表达模式的调控模式。结果表明，在人绒毛癌细胞中，IRGS可以分为几类，每一类都受到不同的抑制机制的影响。因此，这项研究中确定的调控模式表明，人滋养层细胞和绒毛癌细胞可能通过使用几种重叠的机制来阻止irg的表达，从而逃避暴露于干扰素-γ的潜在有害后果。
The pro‐inflammatory cytokine interferon‐γ(IFN‐γ) is critical for activating innate and adaptive immunity against tumours and intracellular pathogens. Interferon‐γis secreted at the fetal–maternal interface in pregnant women and mice. The outer layer of the placenta in contact with maternal blood is composed of semi‐allogeneic trophoblast cells, which constitute the fetal component of the fetal–maternal interface. The simultaneous presence of pro‐inflammatory IFN‐γand trophoblast cells at the fetal–maternal interface appears to represent an immunological paradox, for trophoblastic responses to IFN‐γcould potentially lead to activation of maternal immunity and subsequent attack of the placenta. However, our previous studies demonstrate that IFN‐γresponsive gene (IRG) expression is negatively regulated in human and mouse trophoblast cells. In human cytotrophoblast and trophoblast‐derived choriocarcinoma cells, janus kinase signalling is blocked by protein tyrosine phosphatases (PTPs), whereas in mouse trophoblast, histone deacetylases (HDACs) inhibit IRG expression. Here, we used genome‐wide transcriptional profiling to investigate the collective roles of PTPs and HDACs on regulation of IRG expression in human choriocarcinoma cells. Logic‐rules were optimized to derive regulatory modes governing gene expression patterns observed upon different combinations of treatment with PTP and HDAC inhibitors. The results demonstrate that IRGs can be divided into several categories in human choriocarcinoma cells, each of which is subject to distinct mechanisms of repression. Hence, the regulatory modes identified in this study suggest that human trophoblast and choriocarcinoma cells may evade the potentially deleterious consequences of exposure to IFN‐γby using several overlapping mechanisms to block IRG expression.