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致癌性染色体外DNA作为移动增强子来全面放大染色体转录
作者:小柯机器人 发布时间:2021/4/11 23:58:43

美国杰克逊基因医学实验室Chia-Lin Wei、Roel G.W. Verhaak等研究人员合作发现,致癌性染色体外DNA作为移动增强子来全面放大染色体转录。该项研究成果于2021年4月8日在线发表在《癌细胞》杂志上。

研究人员利用ChIA-PET和ChIA-Drop染色质相互作用测定来表征了影响癌症转录程序的全基因组染色体外环状DNA(ecDNA)介导的染色质接触。胶质母细胞瘤患者来源的神经球和前列腺癌细胞培养物中的ecDNA具有广泛的ecDNA内部和全基因组染色体相互作用的特征。ecDNA-染色质接触灶的特征在于广泛的高水平H3K27ac信号,主要集中在表达水平提高的染色体基因上。前列腺癌细胞具有由特征增强子组成的合成ecDNA环,导致染色体基因转录的全基因组激活。

以单分子分辨率解析ecDNA的染色体靶标表明,在ecDNA指导的相互作用网络内的空间聚集与活跃表达的癌基因直接存在关联。这些结果表明,ecDNA可以作为移动转录增强子来促进肿瘤进展,并在癌症中显示出潜在的合成非整倍体转录调控机制 。

据介绍,ecDNA作为癌症基因组中的一种普遍存在但表征不多的致癌性改变而出现。

附:英文原文

Title: Oncogenic extrachromosomal DNA functions as mobile enhancers to globally amplify chromosomal transcription

Author: Yanfen Zhu, Amit D. Gujar, Chee-Hong Wong, Harianto Tjong, Chew Yee Ngan, Liang Gong, Yi-An Chen, Hoon Kim, Jihe Liu, Meihong Li, Adam Mil-Homens, Rahul Maurya, Chris Kuhlberg, Fanyue Sun, Eunhee Yi, Ana C. deCarvalho, Yijun Ruan, Roel G.W. Verhaak, Chia-Lin Wei

Issue&Volume: 2021-04-08

Abstract: Extrachromosomal, circular DNA (ecDNA) is emerging as a prevalent yet less characterizedoncogenic alteration in cancer genomes. We leverage ChIA-PET and ChIA-Drop chromatininteraction assays to characterize genome-wide ecDNA-mediated chromatin contacts thatimpact transcriptional programs in cancers. ecDNAs in glioblastoma patient-derivedneurosphere and prostate cancer cell cultures are marked by widespread intra-ecDNAand genome-wide chromosomal interactions. ecDNA-chromatin contact foci are characterizedby broad and high-level H3K27ac signals converging predominantly on chromosomal genesof increased expression levels. Prostate cancer cells harboring synthetic ecDNA circlescomposed of characterized enhancers result in the genome-wide activation of chromosomalgene transcription. Deciphering the chromosomal targets of ecDNAs at single-moleculeresolution reveals an association with actively expressed oncogenes spatially clusteredwithin ecDNA-directed interaction networks. Our results suggest that ecDNA can functionas mobile transcriptional enhancers to promote tumor progression and manifest a potentialsynthetic aneuploidy mechanism of transcription control in cancer.

DOI: 10.1016/j.ccell.2021.03.006

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00164-1

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx