來自武漢大學(xué)生命科學(xué)學(xué)院，華中科技大學(xué)等處的研究人員發(fā)現(xiàn)在免疫信號轉(zhuǎn)導(dǎo)通路的一種新機制：表觀遺傳因子選擇性調(diào)控特定基因的激活,，是信號轉(zhuǎn)導(dǎo)通路下游的重要調(diào)節(jié)因素之一,，這一研究成果將表觀遺傳學(xué)與下游基因調(diào)控聯(lián)系在了一起，對于免疫系統(tǒng)研究等方面具有重要意義,，相關(guān)成果公布在國際著名細胞生物學(xué)研究雜志Journal of Cell Science上,。
文章的通訊作者是武漢大學(xué)生命科學(xué)學(xué)院吳旻教授和李聯(lián)運副教授，第一作者為王翔和朱坤,，其中吳旻教授是武漢大學(xué)2009年引進的青年人才,，回國后陸續(xù)申請到2項國家自然科學(xué)基金和參加973項目的研究課題，這兩年已有三篇SCI論文發(fā)表,。
表觀遺傳學(xué)主要研究染色質(zhì)上的蛋白質(zhì)和共價修飾在生命活動中的功能,。MLL1（Myeloid/lymphoid or Mixed-lineage Leukemia 1）是催化組蛋白H3第四位賴氨酸（H3K4）的甲基化酶，其突變可以造成白血病的發(fā)生,。NF-κB信號通路的激活在免疫系統(tǒng)發(fā)育,、拮抗細胞凋亡和白血病發(fā)生等過程中，起著關(guān)鍵作用,。
在這篇文章中,，研究人員發(fā)現(xiàn)了MLL1與NF-κB分子之間存在相互作用。在上游信號刺激后,，NF-κB分子被激活,，并被轉(zhuǎn)運到細胞核內(nèi)。同時與之相互作用的MLL1蛋白也被帶到了靶基因上,。然后MLL1通過影響NF-κB信號通路下游靶基因的啟動子上的H3K4甲基化水平,，選擇性調(diào)控NF-κB下游基因的激活。
這一發(fā)現(xiàn)表明MLL1的突變可能通過影響NF-κB信號通路的激活從而導(dǎo)致白血病的發(fā)生,。并且證明哺乳動物細胞中,，組蛋白修飾及其修飾酶通過與特定信號通路的效應(yīng)分子相互作用調(diào)節(jié)了下游基因的激活，提示表觀遺傳因子選擇性地調(diào)控特定基因的激活是信號轉(zhuǎn)導(dǎo)通路下游的重要調(diào)節(jié)因素之一,。(生物谷Bioon.com)
doi: 10.1242/jcs.103531
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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.
