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Cell Syst. 2018 Nov 28;7(5):482-495.e10. doi: 10.1016/j.cels.2018.09.003. Epub 2018 Nov 7.

Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency.

Author information

1
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany. Electronic address: aleksandra.pekowska@embl.de.
2
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
3
European Molecular Biology Laboratory (EMBL), Cell Biology and Biophysics Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany.
4
Genomics & Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
5
Genomics & Immunity, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Center for Cancer Research, NCI, National Institutes of Health, Bethesda, MD 20892, USA.
6
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany; Stanford Genome Technology Center, 855 California Ave, Palo Alto, CA 94305, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
7
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany; European Molecular Biology Laboratory (EMBL), European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK; Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK. Electronic address: bertone@stemcells.cam.ac.uk.
8
European Molecular Biology Laboratory (EMBL), Genome Biology Unit, Meyerhofstrasse 1, Heidelberg 69117, Germany. Electronic address: whuber@embl.de.

Abstract

The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super-resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives. We found that loss of pluripotency is accompanied by widespread gain of structural loops. This general architectural change correlates with enhanced binding of CTCF and cohesins and more pronounced insulation of contacts across chromatin boundaries in lineage-committed cells. Reprogramming NSCs to pluripotency restores the unique features of ESC domain topology. Domains defined by the anchors of loops established upon differentiation are enriched for developmental genes. Chromatin loop formation is a pervasive structural alteration to the genome that accompanies exit from pluripotency and delineates the spatial segregation of developmentally regulated genes.

KEYWORDS:

CTCF; CTCF loops; chromatin architecture; chromatin loops; chromatin structure; differentiation; pluripotency; topologically associating domains

PMID:
30414923
PMCID:
PMC6327227
DOI:
10.1016/j.cels.2018.09.003
[Indexed for MEDLINE]
Free PMC Article

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