Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Immunity. 2014 Apr 17;40(4):477-89. doi: 10.1016/j.immuni.2014.04.004.
We identified three retinoid-related orphan receptor gamma t (RORγt)-specific inhibitors that suppress T helper 17 (Th17) cell responses, including Th17-cell-mediated autoimmune disease. We systemically characterized RORγt binding in the presence and absence of drugs with corresponding whole-genome transcriptome sequencing. RORγt acts as a direct activator of Th17 cell signature genes and a direct repressor of signature genes from other T cell lineages; its strongest transcriptional effects are on cis-regulatory sites containing the RORα binding motif. RORγt is central in a densely interconnected regulatory network that shapes the balance of T cell differentiation. Here, the three inhibitors modulated the RORγt-dependent transcriptional network to varying extents and through distinct mechanisms. Whereas one inhibitor displaced RORγt from its target loci, the other two inhibitors affected transcription predominantly without removing DNA binding. Our work illustrates the power of a system-scale analysis of transcriptional regulation to characterize potential therapeutic compounds that inhibit pathogenic Th17 cells and suppress autoimmunity.
我们鉴定出三种视黄酸相关孤儿受体γ t（RORγt）特异性抑制剂，它们可抑制辅助性 T 细胞 17（Th17）细胞应答，包括 Th17 细胞介导的自身免疫性疾病。我们通过相应的全基因组转录组测序，对有药物和无药物存在情况下的 RORγt 结合进行了系统表征。RORγt 作为 Th17 细胞特征基因的直接激活子，以及其他 T 细胞谱系特征基因的直接阻遏子发挥作用；其最强的转录效应是在包含 RORα 结合基序的顺式调控位点上。RORγt 处于一个密集的相互关联的调控网络的中心，该网络决定了 T 细胞分化的平衡。在这里，三种抑制剂以不同的程度和机制调节 RORγt 依赖性转录网络。一种抑制剂将 RORγt 从其靶位上置换下来，而另外两种抑制剂则主要通过不消除 DNA 结合来影响转录。我们的工作说明了对转录调控进行系统规模分析以鉴定潜在的治疗性化合物的威力，这些化合物可抑制致病性 Th17 细胞并抑制自身免疫。
