B细胞活化分化为产生抗体的浆细胞之前需要经过生发中心反应才能产生高亲和力抗体，因此生发中心反应是B细胞活化与分化的重要环节。转录抑制因子Bcl6是促进B细胞活化后分化为生发中心B细胞的核心转录因子，然而其表达调控机制尚没有得到非常深入的研究。表观调控与GC反应密切相关。组蛋白H3K36三甲基化修饰的功能主要包括抑制基因过度转录和内部转录起始，调控mRNA可变剪切等，然而其在免疫系统中尤其是生发中心B细胞分化中的功能目前还不清楚。Setd2是已知的唯一介导H3K36三甲基化修饰的酶。在本项目中，我们初步发现特异性敲除生发中心B 细胞中的Setd2导致生发中心B细胞显著减少并且Bcl6表达降低。机制上我们初步发现Setd2可能通过调控转录因子Mef2b的mRNA可变剪切来保证Bcl6的表达从而促进生发中心B细胞分化。在此基础上，我们将进一步研究Setd2调控生发中心B细胞分化的分子机制。

B cell mediated antibody response is critical for pathogen protection. Generation of high-affinity protective antibody is predominantly dependent on germinal center (GC) response, and therefore GC response is an essential event during B cell activation and differentiation. The transcription factor Bcl6 is the master regulatory molecule for GC B cell differentiation. However, the molecular mechanism underlying Bcl6 expression regulation remains incompletely defined. Epigenetic regulation has been reported to be critically involved in GC response. However, the role of the H3K36me3 modification in GC response remains undefined yet. The major roles of H3K36me3 are associated with inhibiting cryptic transcription and mRNA alternative splicing. Setd2 is so far the only methyltransferase for H3K36me3 modification. In this proposal, we initially found that Setd2 is required for GC B cell response. Reduction of GC is associated with decreased Bcl6 expression. Mechanistically, we found that Setd2 ablation leads to altered Mef2b alternative splicing, which is critical for Bcl6 expression. Based on these data, we would further explore the underlying mechanism for the role of Setd2 and H3K36me3 in GC response.