LINT, a Novel dL(3)mbt-Containing Complex, Represses Malignant Brain Tumour Signature Genes
LINT, a Novel dL(3)mbt-Containing Complex, Represses Malignant Brain Tumour Signature Genes
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DOI：
10.1371/journal.pgen.1002676
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发表时间：
2012-05-01
期刊：
影响因子：
4.5
通讯作者：
Brehm, Alexander
中科院分区：
文献类型：
--
作者：
Meier, Karin;Mathieu, Eve-Lyne;Brehm, Alexander
l（3）mbt肿瘤抑制基因的突变导致果蝇幼虫脑的过度增殖。最近，l（3）mbt突变体中不同基因类的去阻遏被证明是转化的原因。然而，dL（3）mbt介导的基因抑制的分子机制尚不清楚。在这里，我们识别出LINT，即果蝇的主要dL（3）mbt复合体。LINT有三个核心亚基-dL（3）mbt、dCoREST和dLint-1-并在细胞系、胚胎和幼虫脑中表达。使用全基因组ChIP-Seq分析，我们表明dLint-1与肿瘤相关靶基因的TSS紧密结合。LINT核心亚基的消耗导致这些基因的去阻遏。相反，组蛋白去乙酰化酶、组蛋白甲基化酶和组蛋白去甲基化酶活性不需要维持阻遏。我们的研究结果支持LINT通过限制启动子进入抑制脑肿瘤相关靶基因的直接作用。
Mutations in the l(3)mbt tumour suppressor result in overproliferation of Drosophila larval brains. Recently, the derepression of different gene classes in l(3)mbt mutants was shown to be causal for transformation. However, the molecular mechanisms of dL(3)mbt-mediated gene repression are not understood. Here, we identify LINT, the major dL(3) mbt complex of Drosophila. LINT has three core subunits-dL(3) mbt, dCoREST, and dLint-1-and is expressed in cell lines, embryos, and larval brain. Using genome-wide ChIP-Seq analysis, we show that dLint-1 binds close to the TSS of tumour-relevant target genes. Depletion of the LINT core subunits results in derepression of these genes. By contrast, histone deacetylase, histone methylase, and histone demethylase activities are not required to maintain repression. Our results support a direct role of LINT in the repression of brain tumour-relevant target genes by restricting promoter access.