JCS：发现免疫信号转导通路一种新机制

来自武汉大学生命科学学院，华中科技大学等处的研究人员发现在免疫信号转导通路的一种新机制：表观遗传因子选择性调控特定基因的激活，是信号转导通路下游的重要调节因素之一，这一研究成果将表观遗传学与下游基因调控联系在了一起，对于免疫系统研究等方面具有重要意义，相关成果公布在国际著名细胞生物学研究杂志Journal of Cell Science上。

文章的通讯作者是武汉大学生命科学学院吴旻教授和李联运副教授，第一作者为王翔和朱坤，其中吴旻教授是武汉大学2009年引进的青年人才，回国后陆续申请到2项国家自然科学基金和参加973项目的研究课题，这两年已有三篇SCI论文发表。

表观遗传学主要研究染色质上的蛋白质和共价修饰在生命活动中的功能。MLL1（Myeloid/lymphoid or Mixed-lineage Leukemia 1）是催化组蛋白H3第四位赖氨酸（H3K4）的甲基化酶，其突变可以造成白血病的发生。NF-κB信号通路的激活在免疫系统发育、拮抗细胞凋亡和白血病发生等过程中，起着关键作用。

在这篇文章中，研究人员发现了MLL1与NF-κB分子之间存在相互作用。在上游信号刺激后，NF-κB分子被激活，并被转运到细胞核内。同时与之相互作用的MLL1蛋白也被带到了靶基因上。然后MLL1通过影响NF-κB信号通路下游靶基因的启动子上的H3K4甲基化水平，选择性调控NF-κB下游基因的激活。

这一发现表明MLL1的突变可能通过影响NF-κB信号通路的激活从而导致白血病的发生。并且证明哺乳动物细胞中，组蛋白修饰及其修饰酶通过与特定信号通路的效应分子相互作用调节了下游基因的激活，提示表观遗传因子选择性地调控特定基因的激活是信号转导通路下游的重要调节因素之一。

doi: 10.1242/​jcs.103531
PMC:
PMID:

MLL1, a H3K4 methyltransferase, regulates the TNFα-stimulated activation of genes downstream of NF-κB

Xiang Wang1,2,*, Kun Zhu1,2,*, Shangze Li1,2, Yifang Liao3, Runlei Du1,2, Xiaodong Zhang1,2, Hong-Bing Shu1, An-Yuan Guo3, Lianyun Li1,2,‡ and Min Wu1,2,‡

Genes of the mixed lineage leukemia (MLL) family regulate transcription by methylating histone H3K4. Six members of the MLL family exist in humans, including SETD1A, SETD1B and MLL1–MLL4. Each of them plays non-redundant roles in development and disease genesis. MLL1 regulates the cell cycle and the oscillation of circadian gene expression. Its fusion proteins are involved in leukemogenesis. Here, we studied the role of MLL1 in innate immunity and found it selectively regulates the activation of genes downstream of NF-κB mediated by tumor necrosis factor (TNFα) and lipopolysaccharide (LPS). Real-time PCR and genome-wide gene expression profile analysis proved that the deficiency of MLL1 reduced the expression of a group of genes downstream of nuclear factor κB (NF-κB). However, the activation of NF-κB itself was not affected. The MLL1 complex is found both in the nucleus and cytoplasm and is associated with NF-κB. CHIP assays proved that the translocation of MLL1 to chromatin was dependent on NF-κB. Our results suggest that MLL1 is recruited to its target genes by activated NF-κB and regulates their transcription.