miR-155通过组蛋白H3K27me3表观遗传修饰调控溃疡性结肠炎Th17/Treg分化的免疫机制及复方苦参汤的协同作用

Th17/Treg immune imbalance is a key factor leading to the pathogenesis of UC. miR-155 is essential for regulating the differentiation of Th17 and Treg cells. Our previous study found that miR-155 can regulate the differentiation and function of Th17 cells in UC through the histone methyltransferase modified protein Jarid2, but whether miR-155 can directly act on the regulation of Th17 and Treg differentiation by histone has not been reported. At the same time, we found that compound sophorae decoction can treat UC by improving Th17/Treg immune imbalance, but its mechanism of regulating Th17/Treg is not clear. The histone modification is closely related to the transcriptional inhibition and activation of the gene, and the epigenetic modification of histone H3K27me3 directly affects Th17/Treg differentiation. Therefore, this project uses epigenetic modification of histone H3K27me3 as an entry point, combined with molecular biology and immunology, using lentiviral transfection, gene knockout, ChIP detection and other techniques through epigenomics and proteomics analysis. For the first step, we intend to investigate the mechanism of miR-155's effect on the differentiation of Th17/Treg in UC by histone H3K27me3, and then explore the therapeutic mechanism of compound sophorae decoction on UC. This project can provide an important theoretical basis for further explaining the immune disorder mechanism of UC, clarifying the mechanism and popularizing the clinical application of compound sophorae decoction in the treatment of UC.

Th17/Treg失衡是UC发病的关键因素，miR-155对调控Th17和Treg的分化至关重要。我们发现，miR-155能通过组蛋白甲基化酶的修饰蛋白Jarid2调节UC中Th17的分化和功能，但miR-155能否直接作用于组蛋白调控Th17和Treg分化尚未见报道。复方苦参汤能改善UC中Th17/Treg失衡，但其调控机制未明。而组蛋白修饰与基因表达密切相关，其中组蛋白H3K27me3修饰直接影响Th17/Treg分化。因此，本项目以H3K27me3表观遗传修饰为切入点，结合分子生物学和免疫学等方法，利用慢病毒转染、基因敲除、ChIP检测等技术，通过表观基因组学和蛋白组学深入研究miR-155通过H3K27me3作用于UC中Th17/Treg分化的机制和复方苦参汤治疗UC的机理。这为进一步阐释UC的免疫紊乱机制、明确复方苦参汤治疗UC的作用机理及其临床推广应用提供重要理论依据。

Th17/Treg失衡是UC发病的关键因素。我们前期研究结果表明复方苦参汤能明显改善UC中Th17/Treg失衡，减轻UC的肠黏膜炎症，但其调控机制尚未阐明。研究发现，表观遗传学修饰广泛参与UC的发病机制。其中组蛋白修饰可以调节UC肠黏膜的免疫功能，而组蛋白H3K27me3修饰能直接影响Th17/Treg的分化。因此，本项目以H3K27me3表观遗传修饰为切入点，结合分子生物学和免疫学等方法，通过表观基因组学和蛋白组学深入研究组蛋白H3K27me3的甲基化酶和去甲基化酶作用于UC中Th17/Treg分化的机制和复方苦参汤的协同作用机理。我们通过预实验筛选出组蛋白H3K27me3的去甲基化酶Jmjd3，以Jmjd3/H3K27me3为靶点，采用Jmjd3抑制剂GSK-J1阻断H3K27me3的表达，进而观察其在UC中对其下游Th17/Treg免疫失衡的影响。我们的结果表明，Jmjd3、H3K27me3在UC中均异常表达；阻断Jmjd3/H3K27me3，UC中Th17细胞的过度分化明显受到抑制；而Treg细胞的分化则明显增加，这可能是Jmjd3抑制剂治疗UC的关键机制，同时复方苦参汤起到协同增效作用。这为进一步深入阐释UC的免疫紊乱机制、明确复方苦参汤治疗UC的作用机理及其临床推广应用提供了重要理论依据。