科学家揭示功能性增强子的功能 作者： 发布时间：/11/22 20:24:01 美国凯斯西储大学医学院Peter C. Scacheri和加州大学Jeremy N. Rich研究团队合作发现，功能性增强子调控染色体外原癌基因的扩增。这一研究成果11月21日在线发表在国际学术期刊《细胞》上。
利用新的计算方法，研究人员发现横跨五种癌症的扩增癌基因附近非编码DNA共扩增的显著特征。 在胶质母细胞瘤中，EGFR优先与其在来源细胞中的具有活性的两个内源性增强子共同扩增。这些调节元件、它们之间的相互作用及其对细胞适应性的贡献在高水平环状染色体外DNA扩增中也存在。使用CRISPR干扰筛选方法对基因座进行探究，揭示了影响细胞适应性的多种其他因素。
适应性依存关系模式反映了调控元件的重排，以及伴随着染色体外增强子上染色质拓扑结构的重塑。该研究表明，致癌基因扩增受非编码基因组调控依赖性的影响。
据了解，原癌基因附近非编码区的扩增在很大程度上被忽略。
附：英文原文
Title: Functional Enhancers Shape Extrachromosomal Oncogene Amplifications
Author: Andrew R. Morton, Nergiz Dogan-Artun, Zachary J. Faber, Graham MacLeod, Cynthia F. Bartels, Megan S. Piazza, Kevin C. Allan, Stephen C. Mack, Xiuxing Wang, Ryan C. Gimple, Qiulian Wu, Brian P. Rubin, Shashirekha Shetty, Stephane Angers, Peter B. Dirks, Richard C. Sallari, Mathieu Lupien, Jeremy N. Rich, Peter C. Scacheri
Issue Volume: November 21,
Abstract: Non-coding regions amplified beyond oncogene borders have largely been ignored. Usinga computational approach, we find signatures of significant co-amplification of non-codingDNA beyond the boundaries of amplified oncogenes across five cancer types. In glioblastoma,EGFR is preferentially co-amplified with its two endogenous enhancer elements active inthe cell type of origin. These regulatory elements, their contacts, and their contributionto cell fitness are preserved on high-level circular extrachromosomal DNA amplifications.Interrogating the locus with a CRISPR interference screening approach reveals a diversityof additional elements that impact cell fitness. The pattern of fitness dependenciesmirrors the rearrangement of regulatory elements and accompanying rewiring of thechromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogeneamplifications are shaped by regulatory dependencies in the non-coding genome.
DOI: 10.1016/j.cell..10.039
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期刊信息 Cell：《细胞》，创刊于1974年。隶属于细胞出版社，最新IF：36.216官方网址：投稿链接：
