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Myc的选择性基因调控

摘要 : 两个独立研究小组在新研究中表明,哺乳动物Myc致癌蛋白受其他各种转录因子所调节,通过调控特定类别的基因来发挥作用的。相关文章发表于2014年7月9日的《Nature》杂志上。

哺乳动物Myc致癌蛋白是与数千个启动子相结合的一种转录因子。关于Myc 功能的两个当前模型提出,它要么是转录的一个基因特异性调控因子,要么是所有活性基因的一个普遍性放大因子。

在本期Nature上发表文章的两个小组提供了支持以下观点的证据:Myc 调控特定基因。

Arianna Sabò 等人分析了在小鼠的B-细胞淋巴瘤发生过程中Myc的基因组分布及RNA表达特征;Susanne Walz等人对正常细胞和被Myc改变的肿瘤细胞做了对比。

虽然这两个小组都发现Myc的表达能导致基因表达的普遍增加,但该效应是间接的。受其他各种转录因子所调制,Myc似乎主要是通过调控特定类别的基因来发挥作用的。

原文摘要:

Activation and repression by oncogenic MYC shape tumour-specific gene expression profiles

Susanne Walz, Francesca Lorenzin, Jennifer Morton, Katrin E. Wiese, Björn von Eyss,Steffi Herold, Lukas Rycak, Hélène Dumay-Odelot, Saadia Karim, Marek Bartkuhn, Frederik Roels, Torsten Wüstefeld, Matthias Fischer, Martin Teichmann, Lars Zender, Chia-Lin Wei,Owen Sansom, Elmar Wolf & Martin Eilers

In mammalian cells, the MYC oncoprotein binds to thousands of promoters. During mitogenic stimulation of primary lymphocytes, MYC promotes an increase in the expression of virtually all genes. In contrast, MYC-driven tumour cells differ from normal cells in the expression of specific sets of up- and downregulated genes that have considerable prognostic value. To understand this discrepancy, we studied the consequences of inducible expression and depletion of MYC in human cells and murine tumour models. Changes in MYC levels activate and repress specific sets of direct target genes that are characteristic of MYC-transformed tumour cells. Three factors account for this specificity. First, the magnitude of response parallels the change in occupancy by MYC at each promoter. Functionally distinct classes of target genes differ in the E-box sequence bound by MYC, suggesting that different cellular responses to physiological and oncogenic MYC levels are controlled by promoter affinity. Second, MYC both positively and negatively affects transcription initiation independent of its effect on transcriptional elongation. Third, complex formation with MIZ1 (also known as ZBTB17) mediates repression of multiple target genes by MYC and the ratio of MYC and MIZ1 bound to each promoter correlates with the direction of response.

Selective transcriptional regulation by Myc in cellular growth control and lymphomagenesis

Arianna Sabò, Theresia R. Kress, Mattia Pelizzola, Stefano de Pretis, Marcin M. Gorski,Alessandra Tesi, Marco J. Morelli, Pranami Bora, Mirko Doni, Alessandro Verrecchia,Claudia Tonelli, Giovanni Fagà, Valerio Bianchi, Alberto Ronchi, Diana Low, Heiko Müller,Ernesto Guccione, Stefano Campaner & Bruno Amati

The c-myc proto-oncogene product, Myc, is a transcription factor that binds thousands of genomic loci. Recent work suggested that rather than up- and downregulating selected groups of genes, Myc targets all active promoters and enhancers in the genome (a phenomenon termed ‘invasion’) and acts as a general amplifier of transcription. However, the available data did not readily discriminate between direct and indirect effects of Myc on RNA biogenesis. We addressed this issue with genome-wide chromatin immunoprecipitation and RNA expression profiles during B-cell lymphomagenesis in mice, in cultured B cells and fibroblasts. Consistent with long-standing observations, we detected general increases in total RNA or messenger RNA copies per cell (hereby termed ‘amplification’) when comparing actively proliferating cells with control quiescent cells: this was true whether cells were stimulated by mitogens (requiring endogenous Myc for a proliferative response) or by deregulated, oncogenic Myc activity. RNA amplification and promoter/enhancer invasion by Myc were separable phenomena that could occur without one another. Moreover, whether or not associated with RNA amplification, Myc drove the differential expression of distinct subsets of target genes. Hence, although having the potential to interact with all active or poised regulatory elements in the genome, Myc does not directly act as a global transcriptional amplifier. Instead, our results indicate that Myc activates and represses transcription of discrete gene sets, leading to changes in cellular state that can in turn feed back on global RNA production and turnover.

对应Nature杂志: 2014年7月24日Nature杂志精选

来源: Nature中文 浏览次数:176

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