title: CTCF-Mediated Human 3D Genome Architecture Reveals Chromatin Topology for Transcription.
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.
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Zhonghui
authors.initials: Z
authors.lastname: Tang
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Oscar Junhong
authors.initials: OJ
authors.lastname: Luo
authors.affiliation: 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.
authors.forename: Xingwang
authors.initials: X
authors.lastname: Li
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Meizhen
authors.initials: M
authors.lastname: Zheng
authors.affiliation: 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.
authors.forename: Jacqueline Jufen
authors.initials: JJ
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Szalaj
authors.affiliation: Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland.
authors.forename: Pawel
authors.initials: P
authors.lastname: Trzaskoma
authors.affiliation: Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland.
authors.forename: Adriana
authors.initials: A
authors.lastname: Magalska
authors.affiliation: Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland.
authors.forename: Jakub
authors.initials: J
authors.lastname: Wlodarczyk
authors.affiliation: Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland.
authors.forename: Blazej
authors.initials: B
authors.lastname: Ruszczycki
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Michalski
authors.affiliation: 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.
authors.forename: Emaly
authors.initials: E
authors.lastname: Piecuch
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Danjuan
authors.initials: D
authors.lastname: Wang
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Simon Zhongyuan
authors.initials: SZ
authors.lastname: Tian
authors.affiliation: Université Paris-Diderot-Paris 7, Centre National de la Recherche Scientifique and Institut Jacques Monod, 15 rue Hélène Brion, 75205 Paris Cedex, France.
authors.forename: May
authors.initials: M
authors.lastname: Penrad-Mobayed
authors.affiliation: Centre National de la Recherche Scientifique and Muséum National d'Histoire Naturelle, 57 Rue Cuvier, 75231 Paris Cedex, France.
authors.forename: Laurent M
authors.initials: LM
authors.lastname: Sachs
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Xiaoan
authors.initials: X
authors.lastname: Ruan
authors.affiliation: Joint Genome Institute, 2800 Mitchell Drive, Walnut Creek, CA 94598, USA.
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Wei
authors.affiliation: The Jackson Laboratory for Genomic Medicine, 10 Discovery Drive, Farmington, CT 06030, USA.
authors.forename: Edison T
authors.initials: ET
authors.lastname: Liu
authors.affiliation: Nencki Institute of Experimental Biology, 3 Pasteur Street, 02-093 Warsaw, Poland.
authors.forename: Grzegorz M
authors.initials: GM
authors.lastname: Wilczynski
authors.affiliation: Centre of New Technologies, University of Warsaw, S. Banacha 2c, 02-097 Warsaw, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Plewczynski
authors.affiliation: 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.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Ruan
mesh_terms: D000818:Animals; D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D002875:Chromosomes / Q000378:metabolism; D042003:DNA Packaging; D015894:Genome, Human; D006801:Humans; D012319:RNA Polymerase II / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D012455:Salamandridae; D014158:Transcription, Genetic; D000097722:Cohesins
chemical_list: D000076246:CCCTC-Binding Factor; D018797:Cell Cycle Proteins; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D012319:RNA Polymerase II; D012097:Repressor Proteins; D000097722:Cohesins; C000619697:CTCF protein, human