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CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription
- Tang, Zhonghui, Luo, Oscar Junhong, Li, Xingwang, Zheng, Meizhen, Zhu, Jacqueline Jufen, Szalaj, Przemyslaw, Trzaskoma, Pawel, Magalska, Adriana, Wlodarczyk, Jakub, Ruszczycki, Blazej, Michalski, Paul, Piecuch, Emaly, Wang, Ping, Wang, Danjuan, Tian, Simon Zhongyuan, Penrad-Mobayed, May, Sachs, Laurent M., Ruan, Xiaoan, Wei, Chia-Lin, Liu, Edison T., Wilczynski, Grzegorz M., Plewczynski, Dariusz, Li, Guoliang, Ruan, Yijun
- Cell 2015 v.163 pp. 1611-1627
- DNA-directed RNA polymerase, chromatin, disease resistance, gene expression, genes, haplotypes, humans, models, topology, transcription (genetics)
- Spatial genome organization and its effect on transcription remains a fundamental question. We applied an advanced chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) strategy to comprehensively map higher-order chromosome folding and specific chromatin interactions mediated by CCCTC-binding factor (CTCF) and RNA polymerase II (RNAPII) with haplotype specificity and nucleotide resolution in different human cell lineages. We find that CTCF/cohesin-mediated interaction anchors serve as structural foci for spatial organization of constitutive genes concordant with CTCF-motif orientation, whereas RNAPII interacts within these structures by selectively drawing cell-type-specific genes toward CTCF foci for coordinated transcription. Furthermore, we show that haplotype variants and allelic interactions have differential effects on chromosome configuration, influencing gene expression, and may provide mechanistic insights into functions associated with disease susceptibility. 3D genome simulation suggests a model of chromatin folding around chromosomal axes, where CTCF is involved in defining the interface between condensed and open compartments for structural regulation. Our 3D genome strategy thus provides unique insights in the topological mechanism of human variations and diseases.