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新方法从基因组规模的纳米孔测序中鉴别出协同的高阶三维染色质构象
2022-05-31 13:14

美国纽约基因组中心Marcin Imieliński研究团队从基因组规模的纳米孔测序中鉴别出协同的高阶三维染色质构象。这一研究成果于2022年5月30日在线发表在国际学术期刊《自然—生物技术》上。

研究人员表示,两个以上基因组位点之间的高阶三维(3D)相互作用在人类染色质中很常见,但它们在基因调控中的作用还不清楚。以前的高阶三维染色质检测要么测量整个基因组的远端相互作用,要么测量选定目标的近端相互作用。

为了解决这个问题,研究人员开发了Pore-C,它结合了染色质构象捕获和纳米孔测序的串联体,在基因组尺度上分析近端高阶染色质接触。研究人员还开发了统计方法Chromunity,以确定高阶接触频率明显高于背景("协同效应")的基因组位点集。将这些方法应用于人类细胞系,研究人员发现协同作用在活跃的染色质中的增强子和启动子中以及在高转录和线型定义基因中富集。在前列腺癌细胞中,这些包括雄性激素驱动的转录因子的结合点和雄性激素调节的基因的启动子。相对于同一基因位点的成对接触,高表达基因中的高阶接触被去甲基化。乳腺癌细胞中的协同作用与Tyfonas有关,这是一类复杂的DNA扩增子。

这些结果严格地将全基因组范围内的高阶三维相互作用与确定谱系的转录程序联系起来,并将Pore-C和Chromunity作为评估高阶基因组结构的可扩展方法。

附:英文原文

Title: Identifying synergistic high-order 3D chromatin conformations from genome-scale nanopore concatemer sequencing

Author: Deshpande, Aditya S., Ulahannan, Netha, Pendleton, Matthew, Dai, Xiaoguang, Ly, Lynn, Behr, Julie M., Schwenk, Stefan, Liao, Will, Augello, Michael A., Tyer, Carly, Rughani, Priyesh, Kudman, Sarah, Tian, Huasong, Otis, Hannah G., Adney, Emily, Wilkes, David, Mosquera, Juan Miguel, Barbieri, Christopher E., Melnick, Ari, Stoddart, David, Turner, Daniel J., Juul, Sissel, Harrington, Eoghan, Imieliski, Marcin

Issue&Volume: 2022-05-30

Abstract: High-order three-dimensional (3D) interactions between more than two genomic loci are common in human chromatin, but their role in gene regulation is unclear. Previous high-order 3D chromatin assays either measure distant interactions across the genome or proximal interactions at selected targets. To address this gap, we developed Pore-C, which combines chromatin conformation capture with nanopore sequencing of concatemers to profile proximal high-order chromatin contacts at the genome scale. We also developed the statistical method Chromunity to identify sets of genomic loci with frequencies of high-order contacts significantly higher than background (‘synergies’). Applying these methods to human cell lines, we found that synergies were enriched in enhancers and promoters in active chromatin and in highly transcribed and lineage-defining genes. In prostate cancer cells, these included binding sites of androgen-driven transcription factors and the promoters of androgen-regulated genes. Concatemers of high-order contacts in highly expressed genes were demethylated relative to pairwise contacts at the same loci. Synergies in breast cancer cells were associated with tyfonas, a class of complex DNA amplicons. These results rigorously link genome-wide high-order 3D interactions to lineage-defining transcriptional programs and establish Pore-C and Chromunity as scalable approaches to assess high-order genome structure.

DOI: 10.1038/s41587-022-01289-z

Source: https://www.nature.com/articles/s41587-022-01289-z

Nature Biotechnology:《自然—生物技术》,创刊于1996年。隶属于施普林格·自然出版集团,最新IF:68.164
官方网址:https://www.nature.com/nbt/
投稿链接:https://mts-nbt.nature.com/cgi-bin/main.plex


本期文章:《自然—生物技术》:Online/在线发表

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