Coordinated regulation of Myc trans-activation targets by Polycomb and the Trithorax group protein Ash1.
Coordinated regulation of Myc trans-activation targets by Polycomb and the Trithorax group protein Ash1.
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DOI：
10.1186/1471-2199-8-40
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发表时间：
2007-05-22
影响因子：
--
通讯作者：
Wieschaus E
中科院分区：
文献类型：
--
作者：
Goodliffe JM;Cole MD;Wieschaus E
Myc癌蛋白是一种转录调节因子，其功能对正常发育至关重要。Myc能够与10%的哺乳动物基因组结合，目前尚不清楚发育中的胚胎如何控制其丰富的Myc蛋白的DNA结合，以避免Myc诱导肿瘤发生的潜力。为了鉴定在控制Myc活性中具有潜在作用的染色质结合蛋白，我们建立了果蝇中dMyc活性的遗传测定。我们进行了全基因组的屏幕上使用该检测，并确定了三胸组蛋白质阿什1作为dMyc活性的修饰剂。Ash1是一种组蛋白甲基转移酶，以其在对抗Polycomb抑制中的作用而闻名。使用RNAi在胚胎和Affyssin微阵列，我们表明，ash 1 RNAi导致许多基因的表达增加，这表明它是直接或间接需要在胚胎中的镇压，在其已知的作用，在维持激活。这些基因中的许多基因也在Pc和pho转录物耗尽后类似地响应，如通过Pc和pho RNAi胚胎的并行微阵列分析所确定的，这表明这三个基因是一组共同靶标的低水平表达所需的。此外，许多这些重叠的靶标也被Myc过表达激活。我们确定了第二组基因，其在胚胎中的表达需要Ash1，与其先前确定的维持激活的作用一致。我们发现，这第二组的阿什1目标重叠的Myc和异位Myc的激活克服了他们的要求阿什1。遗传，基因组和染色质免疫沉淀数据表明，Pc，Ash1和Pho需要保持低水平的表达胚胎Myc激活的目标，这是发生，直接或间接，通过不同的染色质修饰的组合模型。
The Myc oncoprotein is a transcriptional regulator whose function is essential for normal development. Myc is capable of binding to 10% of the mammalian genome, and it is unclear how a developing embryo controls the DNA binding of its abundant Myc proteins in order to avoid Myc's potential for inducing tumorigenesis. To identify chromatin binding proteins with a potential role in controlling Myc activity, we established a genetic assay for dMyc activity in Drosophila. We conducted a genome-wide screen using this assay, and identified the Trithorax Group protein Ash1 as a modifier of dMyc activity. Ash1 is a histone methyltransferase known for its role in opposing repression by Polycomb. Using RNAi in the embryo and Affymetrix microarrays, we show that ash1 RNAi causes the increased expression of many genes, suggesting that it is directly or indirectly required for repression in the embryo, in contrast to its known role in maintenance of activation. Many of these genes also respond similarly upon depletion of Pc and pho transcripts, as determined by concurrent microarray analysis of Pc and pho RNAi embryos, suggesting that the three are required for low levels of expression of a common set of targets. Further, many of these overlapping targets are also activated by Myc overexpression. We identify a second group of genes whose expression in the embryo requires Ash1, consistent with its previously established role in maintenance of activation. We find that this second group of Ash1 targets overlaps those activated by Myc and that ectopic Myc overcomes their requirement for Ash1. Genetic, genomic and chromatin immunoprecipitation data suggest a model in which Pc, Ash1 and Pho are required to maintain a low level of expression of embryonic targets of activation by Myc, and that this occurs, directly or indirectly, by a combination of disparate chromatin modifications.
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