RORγt and RORα signature genes in human Th17 cells.
RORγt and RORα signature genes in human Th17 cells.
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DOI：
10.1371/journal.pone.0181868
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Fung-Leung WP
中科院分区：
文献类型：
--
作者：
Castro G;Liu X;Ngo K;De Leon-Tabaldo A;Zhao S;Luna-Roman R;Yu J;Cao T;Kuhn R;Wilkinson P;Herman K;Nelen MI;Blevitt J;Xue X;Fourie A;Fung-Leung WP
RORγt和RORα是rar相关孤儿核受体（ROR）家族的转录因子。它们在Th17细胞中表达，并被认为在Th17分化中发挥作用。尽管RORγt标记基因在小鼠Th17细胞中已经被表征，但关于其在人类Th17细胞中的转录控制的详细信息有限，对RORα标记基因的了解甚至更少，这些基因在人类或小鼠T细胞中都没有报道。在这项研究中，通过RNA测序分析了在Th17偏态条件下激活的人CD4 T细胞的全局基因表达。在这些Th17细胞中发现了RORγt和RORα的特征基因，这些基因被特异性sirna处理以降低RORγt或RORα的表达。我们已经生成了选择性的小分子RORγt调节剂，它们也被用作RORγt特征基因鉴定的药理学工具。我们的研究结果表明，在Th17细胞中，RORγt控制了非常选择性的一些基因的表达，其中大多数基因也受到RORα的调节，尽管影响较弱。关键的Th17基因包括IL-17A、IL-17F、IL-23R、CCL20和CCR6均受rorr γt和rorr α的调控。我们的研究结果表明，rorγ - t和RORα通过调节一组常见的Th17基因，在人类Th17细胞分化中发挥重叠作用。RORγt作为治疗Th17介导的自身免疫性疾病（如牛皮癣）的药物靶点最近已在临床试验中得到证实。我们的研究结果表明，RORα可能参与相同的疾病机制，本报告中鉴定的基因特征可能是追踪调节患者RORγt或RORα活性的化合物的药效学效应的有价值的生物标志物。
RORγt and RORα are transcription factors of the RAR-related orphan nuclear receptor (ROR) family. They are expressed in Th17 cells and have been suggested to play a role in Th17 differentiation. Although RORγt signature genes have been characterized in mouse Th17 cells, detailed information on its transcriptional control in human Th17 cells is limited and even less is known about RORα signature genes which have not been reported in either human or mouse T cells. In this study, global gene expression of human CD4 T cells activated under Th17 skewing conditions was profiled by RNA sequencing. RORγt and RORα signature genes were identified in these Th17 cells treated with specific siRNAs to knock down RORγt or RORα expression. We have generated selective small molecule RORγt modulators and they were also utilized as pharmacological tools in RORγt signature gene identification. Our results showed that RORγt controlled the expression of a very selective number of genes in Th17 cells and most of them were regulated by RORα as well albeit a weaker influence. Key Th17 genes including IL-17A, IL-17F, IL-23R, CCL20 and CCR6 were shown to be regulated by both RORγt and RORα. Our results demonstrated an overlapping role of RORγt and RORα in human Th17 cell differentiation through regulation of a defined common set of Th17 genes. RORγt as a drug target for treatment of Th17 mediated autoimmune diseases such as psoriasis has been demonstrated recently in clinical trials. Our results suggest that RORα could be involved in same disease mechanisms and gene signatures identified in this report could be valuable biomarkers for tracking the pharmacodynamic effects of compounds that modulate RORγt or RORα activities in patients.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
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作者：
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DOI：
10.1621/nrs.07003
发表时间：
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期刊：
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影响因子：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
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影响因子：
32.4
作者：
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