Mammalian genomes contain several billion base pairs of DNA that are packaged in chromatin fibres. At selected gene loci, cohesin complexes have been proposed to arrange these fibres into higher-order structures1,2,3,4,5,6,7, but how important this function is for determining overall chromosome architecture and how the process is regulated are not well understood. Using conditional mutagenesis in the mouse, here we show that depletion of the cohesin-associated protein Wapl8,9 stably locks cohesin on DNA, leads to clustering of cohesin in axial structures, and causes chromatin condensation in interphase chromosomes. These findings reveal that the stability of cohesin–DNA interactions is an important determinant of chromatin structure, and indicate that cohesin has an architectural role in interphase chromosome territories. Furthermore, we show that regulation of cohesin–DNA interactions by Wapl is important for embryonic development, expression of genes such as c-myc (also known as Myc), and cell cycle progression. In mitosis, Wapl-mediated release of cohesin from DNA is essential for proper chromosome segregation and protects cohesin from cleavage by the protease separase, thus enabling mitotic exit in the presence of functional cohesin complexes.
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We dedicate this paper to the memory of B. Peters, who performed the first experiments on Wapl in our laboratory. We are grateful to K. Aumayr, O. F.-Capetillo, T. Hoffmann, M. E. Idarraga-Amado, S. Kueng, T. Kulcsar, M. Leeb, P. Pasierbek, D. Santamaría, G. Schmauss, A. Souabni, H. Tkadletz, K. Wendt and members of the Peters laboratory for discussions and assistance, J. Hutchins for suggesting the term vermicelli, K. Nasmyth for the separase mouse model, and M. Barbacid, T. Cremer, T. Hirano, T. Jenuwein, M. Malumbres and J. Zuber for reagents. T.N. was supported by the European Molecular Biology Organization (EMBO) and the Japanese Society for the Promotion of Science (JSPS). S.H. was supported by funds from the Agence National de la Recherche (JCJC-SVSE2-2011, ChromaTranscript project) and the European Union (FP7-PEOPLE-2011-CIG, ChromaTranscript project). D.A.C. was supported by MFPL VIPS Program (BMWF and City of Vienna). A.V. acknowledges financial support by the Vienna Science and Technology Fund (WWTF) project VRG10-11, the Research Platform Quantum Phenomena and Nanoscale Biological Systems (QuNaBioS) and by Boehringer Ingelheim. Research in the laboratory of J.-M.P. is supported by Boehringer Ingelheim, the Austrian Science Fund (FWF special research program SFB F34 ‘Chromosome Dynamics’, and Wittgenstein award Z196-B20), the Austrian Research Promotion Agency (FFG, Laura Bassi Center for Optimized Structural Studies), the Vienna Science and Technology Fund (WWTF LS09-13), and the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 241548 (MitoSys).
The authors declare no competing financial interests.
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Tedeschi, A., Wutz, G., Huet, S. et al. Wapl is an essential regulator of chromatin structure and chromosome segregation. Nature 501, 564–568 (2013). https://doi.org/10.1038/nature12471
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