m6A识别蛋白YTHDF2通过KDM6B调控炎症反应机制的研究

Strict regulation of bacteria induced inflammatory response is critical for the maintenance of immune homeostasis. However, the function of RNA modification, such as m6A, in regulating inflammatory signaling are largely unknown. We previously report the mechanisms of several key regulator in controlling inflammation, such as NLRP11. We currently find that YTHDF2 selectively inhibits the production of IL-6 in response to bacteria infection in monocytes and macrophages. Furthermore, we demonstrate that YTHDF2 binds to and degrades H3K27 demethylase KDM6B mRNA, and knockout of KDM6B decreases the transcription of IL-6. Thus, we propose the working model: YTHDF2 promotes H3K27me3 level of IL-6 promoter by recognizing and destabilizing m6A-modified KDM6B mRNA，thereby decreasing the transcription of IL-6 and subsequent inhibiting inflammatory response via epigenetic pathway. In conclusion, this project will explore the m6A modification of KDM6B and the mechanism of YTHDF2 inhibits bacteria induced inflammatory response by destabilizing m6A modified KDM6B mRNA. Thus, this project will provide important theoretical basis for studying immune function of m6A and treatment of inflammatory associated diseases.

控制细菌感染诱导的炎症反应对维持机体的免疫稳态至关重要，RNA修饰如m6A如何调控炎症反应是尚未解决的科学问题。申请人前期报道了NLRP11等调控炎症反应的关键分子及其机制，近期预实验发现： 在人的单核和巨噬细胞中m6A识别蛋白YTHDF2 选择性抑制细菌感染诱导的IL-6的产生。并初步证实YTHDF2结合和降解组蛋白H3K27去甲基化酶KDM6B mRNA，而敲除KDM6B抑制IL-6的转录。由此我们提出科学假设： YTHDF2通过识别和降解m6A修饰的KDM6B mRNA来促进IL-6启动子区H3K27me3上调，进而以表观遗传的方式减少IL-6的转录来抑制炎症反应。本项目拟阐明在细菌感染过程中KDM6B mRNA发生m6A修饰的机理，以及YTHDF2降解m6A 修饰的KDM6B mRNA来控制炎症反应的机制。本研究为探明m6A修饰的免疫学功能及炎症相关疾病的治疗提供可靠的理论依据。

m6A甲基化修饰是一种最常见的RNA 表观转录修饰，主要存在于真核生物mRNA，m6A甲基化修饰调控多种生理功能，但m6A甲基化修饰如何调控细菌感染诱导的炎症反应仍不清楚。本项目设立三个研究内容。1，阐明YTHDF2通过选择性抑制IL-6等炎症因子的转录来控制细菌感染诱导的炎症反应；2，揭示YTHDF2通过组蛋白H3K27me3去甲基化酶KDM6B抑制IL-6转录的分子机制；3，探究m6A修饰影响YTHDF2降解KDM6B mRNA的机理。另外本项目进一步阐明了组蛋白H3K27me3如何调控m6A发生的现象和机制。本项目中申请人发现m6A识别蛋白YTHDF2通过去除组蛋白H3K27me3甲基化修饰促进促炎症因子的产生，以及通过去除H3K27me3修饰促进转录过程中m6A修饰的发生。具体机制如下：YTHDF2降解被m6A修饰的KDM6B mRNA，进而去除促炎症因子启动子区H3K27me3修饰，最终抑制促炎症因子的转录。另一方面，H3K27me3抑制转录过程中m6A修饰的发生，KDM6B去除H3K27me3并招募m6A甲基化修饰酶促进转录过程中m6A修饰的发生。本项目的完成将阐明表观转录修饰（m6A甲基化修饰）与表观遗传修饰（组蛋白H3K27me3）通过交互作用调控感染免疫的新机制，为感染免疫治疗提供了新的理论基础。