Beagrie Robert A, Scialdone Antonio, Schueler Markus, Kraemer Dorothee C A, Chotalia Mita, Xie Sheila Q, Barbieri Mariano, de Santiago Inês, Lavitas Liron-Mark, Branco Miguel R, Fraser James, Dostie Josée, Game Laurence, Dillon Niall, Edwards Paul A W, Nicodemi Mario, Pombo Ana
Epigenetic Regulation and Chromatin Architecture Group, Berlin Institute for Medical Systems Biology, Max-Delbrück Centre for Molecular Medicine, Robert-Rössle Straße, Berlin-Buch 13125, Germany.
Genome Function Group, MRC London Institute of Medical Sciences, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK.
Nature. 2017 Mar 23;543(7646):519-524. doi: 10.1038/nature21411. Epub 2017 Mar 8.
The organization of the genome in the nucleus and the interactions of genes with their regulatory elements are key features of transcriptional control and their disruption can cause disease. Here we report a genome-wide method, genome architecture mapping (GAM), for measuring chromatin contacts and other features of three-dimensional chromatin topology on the basis of sequencing DNA from a large collection of thin nuclear sections. We apply GAM to mouse embryonic stem cells and identify enrichment for specific interactions between active genes and enhancers across very large genomic distances using a mathematical model termed SLICE (statistical inference of co-segregation). GAM also reveals an abundance of three-way contacts across the genome, especially between regions that are highly transcribed or contain super-enhancers, providing a level of insight into genome architecture that, owing to the technical limitations of current technologies, has previously remained unattainable. Furthermore, GAM highlights a role for gene-expression-specific contacts in organizing the genome in mammalian nuclei.
基因组在细胞核中的组织方式以及基因与其调控元件的相互作用是转录调控的关键特征，它们的破坏会导致疾病。在此，我们报告一种全基因组方法——基因组结构图谱（GAM），用于基于对大量薄核切片的DNA测序来测量染色质接触及三维染色质拓扑结构的其他特征。我们将GAM应用于小鼠胚胎干细胞，并使用一种称为SLICE（共分离统计推断）的数学模型，识别出活跃基因与增强子之间在非常大的基因组距离上的特定相互作用富集情况。GAM还揭示了全基因组中大量的三向接触，特别是在高转录区域或包含超级增强子的区域之间，这提供了一种由于当前技术的技术限制而以前无法获得的对基因组结构的洞察水平。此外，GAM突出了基因表达特异性接触在哺乳动物细胞核基因组组织中的作用。
