National Key Laboratory of Medical Molecular Biology, Department of Immunology &Center for Immunotherapy, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China.
National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Nat Commun. 2017 Jun 9;8:15818. doi: 10.1038/ncomms15818.
Regulatory T (Treg) cells are important for the maintenance of immune homoeostasis and prevention of autoimmune diseases. Epigenetic modifications have been reported to modulate autoimmunity by altering Treg cell fate. Here we show that the H3K4 methyltransferase Ash1l facilitates TGF-β-induced Treg cell polarization in vitro and protects mice from T cell-mediated colitis in vivo. Ash1l upregulates Smad3 expression by directly targeting Smad3 promoter to increase local H3K4 trimethylation. Furthermore, we identify an lncRNA, namely lnc-Smad3, which interacts with the histone deacetylase HDAC1 and silences Smad3 transcription. After TGF-β stimulation, activated Smad3 suppresses lnc-Smad3 transcription, thereby recovering the Smad3 promoter accessibility to Ash1l. By revealing the opposite regulatory functions of Ash1l and lnc-Smad3 in Smad3 expression, our data provide insights for the epigenetic control of Treg cell fate to potentially aid in the development of therapeutic intervention for autoimmune diseases.
调节性 T（Treg）细胞对于维持免疫稳态和预防自身免疫性疾病非常重要。据报道，表观遗传修饰可以通过改变 Treg 细胞命运来调节自身免疫。在这里，我们显示 H3K4 甲基转移酶 Ash1l 促进 TGF-β 诱导的体外 Treg 细胞极化，并在体内保护小鼠免受 T 细胞介导的结肠炎。Ash1l 通过直接靶向 Smad3 启动子增加局部 H3K4 三甲基化来上调 Smad3 表达。此外，我们鉴定了一种 lncRNA，即 lnc-Smad3，它与组蛋白去乙酰化酶 HDAC1 相互作用并沉默 Smad3 转录。在 TGF-β 刺激后，激活的 Smad3 抑制 lnc-Smad3 转录，从而恢复 Ash1l 对 Smad3 启动子的可及性。通过揭示 Ash1l 和 lnc-Smad3 在 Smad3 表达中的相反调节功能，我们的数据为 Treg 细胞命运的表观遗传控制提供了见解，可能有助于开发自身免疫性疾病的治疗干预措施。
