Cohesin Disrupts Polycomb-Dependent Chromosome Interactions in Embryonic Stem Cells
James D.P. Rhodes,
Angelika Feldmann,
Benjamín Hernández-Rodríguez,
Noelia Díaz,
Jill M. Brown,
Nadezda A. Fursova,
Neil P. Blackledge,
Praveen Prathapan,
Paula Dobrinic,
Miles K. Huseyin,
Aleksander Szczurek,
Kai Kruse,
Kim A. Nasmyth,
Veronica J. Buckle,
Juan M. Vaquerizas,
Robert J. Klose
Affiliations
James D.P. Rhodes
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Angelika Feldmann
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Benjamín Hernández-Rodríguez
Max Planck Institute for Molecular Biomedicine, Roentgenstrasse 20, 48149 Muenster, Germany
Noelia Díaz
Max Planck Institute for Molecular Biomedicine, Roentgenstrasse 20, 48149 Muenster, Germany
Jill M. Brown
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK
Nadezda A. Fursova
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Neil P. Blackledge
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Praveen Prathapan
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Paula Dobrinic
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Miles K. Huseyin
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Aleksander Szczurek
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Kai Kruse
Max Planck Institute for Molecular Biomedicine, Roentgenstrasse 20, 48149 Muenster, Germany
Kim A. Nasmyth
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
Veronica J. Buckle
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK
Juan M. Vaquerizas
Max Planck Institute for Molecular Biomedicine, Roentgenstrasse 20, 48149 Muenster, Germany; MRC London Institute of Medical Sciences, Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, Du Cane Road, London W12 0NN, UK; Corresponding author
Robert J. Klose
Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK; Corresponding author
Summary: How chromosome organization is related to genome function remains poorly understood. Cohesin, loop extrusion, and CCCTC-binding factor (CTCF) have been proposed to create topologically associating domains (TADs) to regulate gene expression. Here, we examine chromosome conformation in embryonic stem cells lacking cohesin and find, as in other cell types, that cohesin is required to create TADs and regulate A/B compartmentalization. However, in the absence of cohesin, we identify a series of long-range chromosomal interactions that persist. These correspond to regions of the genome occupied by the polycomb repressive system and are dependent on PRC1. Importantly, we discover that cohesin counteracts these polycomb-dependent interactions, but not interactions between super-enhancers. This disruptive activity is independent of CTCF and insulation and appears to modulate gene repression by the polycomb system. Therefore, we discover that cohesin disrupts polycomb-dependent chromosome interactions to modulate gene expression in embryonic stem cells. : Using Hi-C, Capture-C, and DNA-FISH, Rhodes et al. discover that interactions between polycomb target genes occur independently of cohesin in embryonic stem cells. This relies on PRC1, and these interactions are disrupted by cohesin-mediated loop extrusion. Upon removal of cohesin, gene repression is enhanced at polycomb-occupied genes with increased interactions. Keywords: cohesin, Polycomb, TADs, loop extrusion, Hi-C, gene regulation
