Two independent modes of chromatin organization revealed by cohesin removal

Wibke Schwarzer, Nezar Abdennur, Anton Goloborodko, Aleksandra Pekowska, Geoffrey Fudenberg, Yann Loe-Mie, Nuno A Fonseca, Wolfgang Huber, Christian H. Haering, Leonid Mirny () and Francois Spitz ()
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Wibke Schwarzer: Developmental Biology Unit. European Molecular Biology Laboratory
Nezar Abdennur: Computational and Systems Biology Program, Massachusetts Institute of Technology
Anton Goloborodko: Massachusetts Institute of Technology
Aleksandra Pekowska: Genome Biology Unit. European Molecular Biology Laboratory
Geoffrey Fudenberg: Institute for Medical Engineering and Sciences, Massachusetts Institute of Technology
Yann Loe-Mie: Institut Pasteur, (Epi)genomics of Animal Development Unit
Nuno A Fonseca: European Bioinformatics Institute. European Molecular Biology Laboratory. Wellcome Trust Genome Campus
Wolfgang Huber: Genome Biology Unit. European Molecular Biology Laboratory
Christian H. Haering: Cell Biology and Biophysics Unit, European Molecular Biology Laboratory
Leonid Mirny: Massachusetts Institute of Technology
Francois Spitz: Developmental Biology Unit. European Molecular Biology Laboratory

Nature, 2017, vol. 551, issue 7678, 51-56

Abstract: Abstract Imaging and chromosome conformation capture studies have revealed several layers of chromosome organization, including segregation into megabase-sized active and inactive compartments, and partitioning into sub-megabase domains (TADs). It remains unclear, however, how these layers of organization form, interact with one another and influence genome function. Here we show that deletion of the cohesin-loading factor Nipbl in mouse liver leads to a marked reorganization of chromosomal folding. TADs and associated Hi-C peaks vanish globally, even in the absence of transcriptional changes. By contrast, compartmental segregation is preserved and even reinforced. Strikingly, the disappearance of TADs unmasks a finer compartment structure that accurately reflects the underlying epigenetic landscape. These observations demonstrate that the three-dimensional organization of the genome results from the interplay of two independent mechanisms: cohesin-independent segregation of the genome into fine-scale compartments, defined by chromatin state; and cohesin-dependent formation of TADs, possibly by loop extrusion, which helps to guide distant enhancers to their target genes.

Date: 2017
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DOI: 10.1038/nature24281

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