Notch ligand Delta-like ligand 4 (DLL4) has been shown to regulate CD4 T-cell differentiation, including regulatory T cells (T_reg). Epigenetic alterations, which include histone modifications, are critical in cell differentiation decisions. Recent genome-wide studies demonstrated that T_reg have increased trimethylation on histone H3 at lysine 4 (H3K4me3) around the T_reg master transcription factor, Foxp3 loci. Here we report that DLL4 dynamically increased H3K4 methylation around the Foxp3 locus that was dependent upon upregulated SET and MYDN domain containing protein 3 (SMYD3). DLL4 promoted Smyd3 through the canonical Notch pathway in iT_reg differentiation. DLL4 inhibition during pulmonary respiratory syncytial virus (RSV) infection decreased Smyd3 expression and Foxp3 expression in T_reg leading to increased Il17a. On the other hand, DLL4 supported Il10 expression in vitro and in vivo, which was also partially dependent upon SMYD3. Using genome-wide unbiased mRNA sequencing, novel sets of DLL4- and Smyd3-dependent differentially expressed genes were discovered, including lymphocyte-activation gene 3 (Lag3), a checkpoint inhibitor that has been identified for modulating Th cell activation. Together, our data demonstrate a novel mechanism of DLL4/Notch-induced Smyd3 epigenetic pathways that maintain regulatory CD4 T cells in viral infections.

中文翻译：

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Notch 配体 Delta-like 4 在病毒感染中诱导 Treg 细胞分化和功能的表观遗传调节。

Notch 配体 Delta 样配体 4 (DLL4) 已显示可调节 CD4 T 细胞分化，包括调节性 T 细胞 (T _reg )。表观遗传改变，包括组蛋白修饰，在细胞分化决定中至关重要。最近的全基因组研究表明，T _{reg在 T reg}主转录因子 Foxp3 基因座周围的赖氨酸 4 (H3K4me3) 上增加了组蛋白 H3 的三甲基化。在这里，我们报告 DLL4 动态增加 Foxp3 基因座周围的 H3K4 甲基化，这取决于上调的 SET 和 MYDN 结构域含有蛋白 3 (SMYD3)。_{DLL4 通过 iT reg}中的规范 Notch 通路促进 Smyd3分化。_{肺呼吸道合胞病毒 (RSV) 感染期间的 DLL4 抑制降低了 T reg}中的 Smyd3 表达和 Foxp3 表达，导致 Il17a 增加。另一方面，DLL4 支持 Il10 在体外和体内的表达，这也部分依赖于 SMYD3。使用全基因组无偏 mRNA 测序，发现了一组新的 DLL4 和 Smyd3 依赖性差异表达基因，包括淋巴细胞激活基因 3 (Lag3)，这是一种已被确定用于调节 Th 细胞激活的检查点抑制剂。总之，我们的数据证明了 DLL4/Notch 诱导的 Smyd3 表观遗传途径的一种新机制，该途径在病毒感染中维持调节性 CD4 T 细胞。