Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity.
Ash1l and lnc-Smad3 coordinate Smad3 locus accessibility to modulate iTreg polarization and T cell autoimmunity.
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Ash1l 和 lnc-Smad3 协调 Smad3 位点可及性以调节 iTreg 极化和 T 细胞自身免疫
DOI：
10.1038/ncomms15818
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发表时间：
2017-06-09
影响因子：
16.6
通讯作者：
Cao X
中科院分区：
文献类型：
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作者：
Xia M;Liu J;Liu S;Chen K;Lin H;Jiang M;Xu X;Xue Y;Liu W;Gu Y;Zhang X;Li Z;Yi L;Qian Y;Zhou C;Li R;Zhang X;Li Z;Cao X
调节性T(Treg)细胞对维持免疫动态平衡和预防自身免疫性疾病具有重要意义。表观遗传修饰已被报道通过改变Treg细胞的命运来调节自身免疫。在这里，我们证明了H3K4甲基转移酶Ash11在体外促进转化生长因子-β诱导的Treg细胞极化，并在体内保护小鼠免受T细胞介导的结肠炎的影响。Ash1通过直接靶向Smad3启动子增加局部H3K4的三甲基化来上调Smad3的表达。此外，我们还鉴定了一个lncRNA，即lnc-Smad3，它与组蛋白脱乙酰基酶HDAC1相互作用，并沉默Smad3的转录。在转化生长因子-β刺激后，激活的Smad3抑制了lnc-Smad3的转录，从而恢复了Smad3启动子对Ash1的可及性。通过揭示Ash1和lnc-Smad3在Smad3表达中相反的调控功能，我们的数据为表观遗传控制Treg细胞命运提供了见解，可能有助于开发对自身免疫性疾病的治疗干预。
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.