Key Points Inducible and constitutive enhancers cooperate to generate transcriptional outputs. Identification of TF binding site clusters is critical in Il13 gene transcription. IL-13 plays a critical role in mediating many biological processes responsible for allergic inflammation. Mast cells express Il13 mRNA and produce IL-13 protein in response to antigenic stimulation. Enhancers are essential in promoting gene transcription and are thought to activate transcription by delivering essential accessory cofactors to the promoter to potentiate gene transcription. However, enhancers mediating Il13 have not been identified. Furthermore, which Il13 enhancers detect signals triggered by antigenic stimulation have not yet been defined. In this study, we identified potential mouse Il13 enhancers using histone modification monomethylation at lysine residue 4 on histone 3 (H3K4me1) chromatin immunoprecipitation sequencing and acetylation at lysine residue 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing. We used Omni–assay for transposase-accessible chromatin sequencing to determine which accessible regions within the potential Il13 enhancers that responded to IgE receptor crosslinking. We also demonstrated that the transcription factor cluster consisting of the NFATC2, STAT5, GATA2, AP1, and RUNX1 binding sites at the proximal Il13 enhancer and the transcription factor cluster consisting of the EGR2 binding site at the distal Il13 E+6.5 enhancer are critical in sensing the signals triggered by antigenic stimulation. Those enhancers, which are responsive to antigenic stimulation and are constitutively active, cooperate to generate greater transcriptional outputs. Our study reveals a novel mechanism underlying how antigenic stimulation induces robust Il13 mRNA expression in mouse mast cells.

中文翻译：

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诱导的 Il13 增强子处的转录因子簇 NFATC2、STAT5、GATA2、AP1、RUNX1 和 EGR2 结合位点介导 Il13 基因转录以响应抗原刺激

关键点 诱导型和组成型增强子合作产生转录输出。TF 结合位点簇的鉴定在 Il13 基因转录中至关重要。IL-13 在介导许多导致过敏性炎症的生物学过程中起关键作用。肥大细胞表达 Il13 mRNA 并响应抗原刺激产生 IL-13 蛋白。增强子在促进基因转录中是必不可少的，并且被认为通过将必需的辅助辅因子递送到启动子以增强基因转录来激活转录。然而，尚未确定介导 Il13 的增强子。此外，尚未确定哪些 Il13 增强子检测由抗原刺激触发的信号。在这项研究中，我们使用组蛋白 3 (H3K4me1) 染色质免疫沉淀测序上赖氨酸残基 4 的组蛋白修饰单甲基化和组蛋白 3 (H3K27ac) 染色质免疫沉淀测序上赖氨酸残基 27 的乙酰化鉴定了潜在的小鼠 Il13 增强子。我们使用 Omni-assay 进行转座酶可及染色质测序以确定潜在 Il13 增强子中哪些可访问区域对 IgE 受体交联有反应。我们还证明了由近端 Il13 增强子处的 NFATC2、STAT5、GATA2、AP1 和 RUNX1 结合位点组成的转录因子簇和由远端 Il13 E+6.5 增强子处的 EGR2 结合位点组成的转录因子簇在感应由抗原刺激触发的信号。那些增强剂，它们对抗原刺激有反应并具有组成性活性，协同产生更大的转录输出。我们的研究揭示了抗原刺激如何在小鼠肥大细胞中诱导强大的 Il13 mRNA 表达的新机制。