A common set of gene regulatory networks links metabolism and growth inhibition
A common set of gene regulatory networks links metabolism and growth inhibition
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DOI：
10.1016/j.molcel.2004.09.037
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发表时间：
2004-11-05
期刊：
影响因子：
16
通讯作者：
Dynlacht, BD
中科院分区：
文献类型：
--
作者：
Cam, H;Balciunaite, E;Dynlacht, BD
通过对转录因子占据的全基因组分析，我们研究了需要 pRB 肿瘤抑制家族的三种哺乳动物生长停滞途径的潜在机制。我们发现p130和E2F4在每种生长停滞条件下协同抑制一组共同的基因，并表明生长停滞是通过抑制一组核心基因来实现的，这些核心基因不仅涉及细胞周期控制，还涉及线粒体生物发生和代谢。基序查找算法预测了 E2F 靶启动子中核呼吸因子 1 (NRF1) 结合位点的存在，全基因组因子结合分析证实了我们的预测。我们发现，NRF1 是一种已知调节线粒体功能相关基因表达的因子，它是大量 E2F 靶基因的共调节因子。我们的研究提供了对 E2F 调节电路的见解，表明因子占据如何预测给定靶基因的表达特征，并揭示人类肿瘤中失调的途径。
Using genome-wide analysis of transcription factor occupancy, we investigated the mechanisms underlying three mammalian growth arrest pathways that require the pRB tumor suppressor family. We found that p130 and E2F4 cooperatively repress a common set of genes under each growth arrest condition and showed that growth arrest is achieved through repression of a core set of genes involved not only in cell cycle control but also mitochondrial biogenesis and metabolism. Motif-finding algorithms predicted the existence of nuclear respiratory factor-1 (NRF1) binding sites in E2F target promoters, and genome-wide factor binding analysis confirmed our predictions. We showed that NRF1, a factor known to regulate expression of genes involved in mitochondrial function, is a coregulator of a large number of E2F target genes. Our studies provide insights into E2F regulatory circuitry, suggest how factor occupancy can predict the expression signature of a given target gene, and reveal pathways deregulated in human tumors.