Lymphocyte Nuclear Biology, NIAMS, NIH, Bethesda, MD 20892, USA.
The Center for Genome Architecture, Baylor College of Medicine, Houston, TX 77030, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Cell. 2018 May 17;173(5):1165-1178.e20. doi: 10.1016/j.cell.2018.03.072. Epub 2018 Apr 26.
Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra-deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development.
黏合蛋白挤压被认为在建立哺乳动物基因组结构中发挥核心作用。然而，其在体内尚未被可视化，因此其功能影响和能量学仍不清楚。我们利用超高深度 Hi-C 技术表明，环域的形成需要黏合蛋白 ATP 酶。然而，一旦形成，环和隔室可以在没有能量输入的情况下维持数小时。引人注目的是，在没有 ATP 的情况下，我们观察到数百个与 CTCF 无关的环的出现，这些环将调控 DNA 连接起来。我们还发现了结构“条纹”，其中一个环的锚点以高频率与整个域相互作用。条纹经常将超级增强子与同源启动子连接起来，在 B 细胞中，它们促进 Igh 转录和重组。条纹锚点是拓扑异构酶介导的损伤的主要热点，这些损伤会促进染色体易位和癌症。在浆细胞瘤中，条纹可以使 Igh 易位的致癌基因失活。我们提出，高等生物已经利用黏合蛋白挤压来增强转录和重组，这对肿瘤的发展有影响。
