The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells.
The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells.
复制标题
组蛋白去甲基酶UTX调节不变天然杀伤T细胞的谱系特异性表观遗传程序。
DOI：
10.1038/ni.3644
复制
发表时间：
2017-02
影响因子：
30.5
通讯作者：
Winau F
中科院分区：
文献类型：
--
作者：
Beyaz S;Kim JH;Pinello L;Xifaras ME;Hu Y;Huang J;Kerenyi MA;Das PP;Barnitz RA;Herault A;Dogum R;Haining WN;Yilmaz ÖH;Passegue E;Yuan GC;Orkin SH;Winau F
不变的自然杀伤T（iNKT）细胞是一种先天性淋巴细胞，可以防止感染，自身免疫性疾病和癌症。然而，对iNKT细胞发育的表观遗传调控知之甚少。在这里，我们表明，H3K27me3组蛋白去甲基化酶UTX是一个必不可少的细胞内因子，控制iNKT谱系特异性基因表达程序和表观遗传景观的去甲基化酶活性依赖的方式。UTX缺陷型iNKT细胞表现出iNKT特征基因的表达受损，这是由于UTX占据的启动子内的激活相关H3K4me3减少和抑制性H3K27me3标记增加。我们鉴定了JunB作为iNKT发育的新调节因子，并表明JunB和iNKT主转录因子PLZF的靶基因表达是UTX依赖的。我们确定了iNKT超级增强子，并证明了UTX介导的超级增强子可及性调节是iNKT谱系定型的关键机制。这些发现揭示了UTX如何通过多种表观遗传机制调节iNKT细胞发育。
Invariant natural killer T (iNKT) cells are innate-like lymphocytes that protect against infection, autoimmune disease and cancer. However, little is known about epigenetic regulation of iNKT cell development. Here, we show that the H3K27me3 histone demethylase UTX is an essential cell-intrinsic factor that controls an iNKT lineage-specific gene expression program and epigenetic landscape in a demethylase activity dependent manner. UTX-deficient iNKT cells exhibited impaired expression of iNKT signature genes due to a decrease in activation-associated H3K4me3 and an increase in repressive H3K27me3 marks within the promoters that UTX occupies. We identified JunB as a novel regulator of iNKT development and show that target gene expression of both JunB and iNKT master transcription factor PLZF was UTX-dependent. We determined iNKT super-enhancers and demonstrated that UTX-mediated regulation of super-enhancer accessibility was a key mechanism for iNKT lineage commitment. These findings reveal how UTX regulates iNKT cell development through multiple epigenetic mechanisms.