Structural Genomics Unit, Bioinformatics and Genomics Department, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Nat Struct Mol Biol. 2011 Jan;18(1):107-14. doi: 10.1038/nsmb.1936. Epub 2010 Dec 5.
We developed a general approach that combines chromosome conformation capture carbon copy (5C) with the Integrated Modeling Platform (IMP) to generate high-resolution three-dimensional models of chromatin at the megabase scale. We applied this approach to the ENm008 domain on human chromosome 16, containing the α-globin locus, which is expressed in K562 cells and silenced in lymphoblastoid cells (GM12878). The models accurately reproduce the known looping interactions between the α-globin genes and their distal regulatory elements. Further, we find using our approach that the domain folds into a single globular conformation in GM12878 cells, whereas two globules are formed in K562 cells. The central cores of these globules are enriched for transcribed genes, whereas nontranscribed chromatin is more peripheral. We propose that globule formation represents a higher-order folding state related to clustering of transcribed genes around shared transcription machineries, as previously observed by microscopy.
我们开发了一种通用方法，将染色体构象捕获碳拷贝（5C）与集成建模平台（IMP）相结合，生成兆碱基尺度上染色质的高分辨率三维模型。我们将此方法应用于人类 16 号染色体上的 ENm008 结构域，该结构域包含α-珠蛋白基因座，在 K562 细胞中表达，而在淋巴母细胞（GM12878）中沉默。这些模型准确地再现了已知的α-珠蛋白基因与其远端调控元件之间的环化相互作用。此外，我们通过使用我们的方法发现，该结构域在 GM12878 细胞中折叠成单个球形构象，而在 K562 细胞中形成两个球形。这些球形的核心区域富含转录基因，而非转录染色质则更靠近外周。我们提出，球形形成代表了一种与转录基因在共享转录机制周围聚集相关的更高阶折叠状态，如先前通过显微镜观察到的那样。
