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Cell. 2015 Dec 17;163(7):1611-27. doi: 10.1016/j.cell.2015.11.024. Epub 2015 Dec 10.

CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription.

Author information

1
The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
2
The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA; National Key Laboratory of Crop Genetic Improvement, College of Life Sciences and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
3
The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA; Department of Genetics and Genome Sciences, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT 06030, USA.
4
Center for Bioinformatics and Data Analysis, Medical University of Bialystok, ul. Jana Kilinskiego 1, 15-089 Bialystok, Poland; I-BioStat, Hasselt University, Agoralaan Building D, 3590 Diepenbeek, Belgium; Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland.
5
Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland.
6
Université Paris-Diderot-Paris 7, Centre National de la Recherche Scientifique and Institut Jacques Monod, 15 rue Hélène Brion, 75205 Paris Cedex, France.
7
Centre National de la Recherche Scientifique and Muséum National d'Histoire Naturelle, 57 Rue Cuvier, 75231 Paris Cedex, France.
8
Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, CA 94598, USA.
9
Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland.
10
National Key Laboratory of Crop Genetic Improvement, College of Life Sciences and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China; College of Informatics, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
11
The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA; National Key Laboratory of Crop Genetic Improvement, College of Life Sciences and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China; Department of Genetics and Genome Sciences, University of Connecticut Health Center, 400 Farmington Avenue, Farmington, CT 06030, USA. Electronic address: yijun.ruan@jax.org.

Abstract

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.

PMID:
26686651
PMCID:
PMC4734140
DOI:
10.1016/j.cell.2015.11.024
[Indexed for MEDLINE]
Free PMC Article

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