Cam Hugh, Balciunaite Egle, Blais Alexandre, Spektor Alexander, Scarpulla Richard C, Young Richard, Kluger Yuval, Dynlacht Brian David
Department of Pathology, MSB 504, New York University School of Medicine and New York University Cancer Institute, 550 First Avenue, New York, NY 10016, USA.
Mol Cell. 2004 Nov 5;16(3):399-411. doi: 10.1016/j.molcel.2004.09.037.
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.
通过对转录因子占据情况进行全基因组分析，我们研究了三种需要pRB肿瘤抑制家族的哺乳动物生长停滞途径的潜在机制。我们发现，在每种生长停滞条件下，p130和E2F4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实现的，这些基因不仅参与细胞周期控制，还参与线粒体生物发生和代谢。基序查找算法预测E2F靶启动子中存在核呼吸因子-1（NRF1）结合位点，全基因组因子结合分析证实了我们的预测。我们表明，NRF1是一种已知调节参与线粒体功能基因表达的因子，是大量E2F靶基因的共调节因子。我们的研究为E2F调控回路提供了见解，提示了因子占据情况如何预测给定靶基因的表达特征，并揭示了人类肿瘤中失调的途径。
