The cohesin acetylation cycle controls chromatin loop length through a PDS5A brake mechanism
van Ruiten, Marjon S.; van Gent, Démi; Sedeño Cacciatore, Ángela; Fauster, Astrid; Willems, Laureen; Hekkelman, Maarten L.; Hoekman, Liesbeth; Altelaar, Maarten; Haarhuis, Judith H.I.; Brummelkamp, Thijn R.; de Wit, Elzo; Rowland, Benjamin D.
(2022) Nature Structural and Molecular Biology, volume 29, issue 6, pp. 586 - 591
(Article)
Abstract
Cohesin structures the genome through the formation of chromatin loops and by holding together the sister chromatids. The acetylation of cohesin’s SMC3 subunit is a dynamic process that involves the acetyltransferase ESCO1 and deacetylase HDAC8. Here we show that this cohesin acetylation cycle controls the three-dimensional genome in human cells.
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ESCO1 restricts the length of chromatin loops, and of architectural stripes emanating from CTCF sites. HDAC8 conversely promotes the extension of such loops and stripes. This role in controlling loop length turns out to be distinct from the canonical role of cohesin acetylation that protects against WAPL-mediated DNA release. We reveal that acetylation controls the interaction of cohesin with PDS5A to restrict chromatin loop length. Our data support a model in which this PDS5A-bound state acts as a brake that enables the pausing and restart of loop enlargement. The cohesin acetylation cycle hereby provides punctuation in the process of genome folding.
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ISSN: 1545-9993
Publisher: Nature Publishing Group
Note: Funding Information: We thank our colleagues for helpful discussions. We thank H. Teunissen, T. van den Brand and M. Panarotto-Périclès for technical assistance, K. Shirahige (The University of Tokyo) for the acetylated SMC3 antibody, S. Rankin (Oklahoma Medical Research Foundation) for the ESCO1 antibody, T. Perrakis for advice on protein structure, M. Vermeulen and I. Santos-Barriopedro for experiments not included in the manuscript and the NKI Genomics Core facility and Flow Cytometry facility for assistance. M.S.v.R. was supported by Boehringer Ingelheim Fonds; M.S.v.R., D.G., Á.S.C. and B.D.R. by the European Research Council (no. ERC 772471—‘CohesinLooping’); J.H.I.H. and L.W. by the Dutch Cancer Society (no. KWF 11665); L.H. and M.A. by the Dutch NWO X-omics Initiative (no. 184.034.019); E.d.W. by the European Research Council (nos. ERC 637587—‘HAP-PHEN’ and ERC 865459—‘FuncDis3D’); and T.R.B. by the Dutch Research Council (no. 016.Vici.170.033). Funding Information: We thank our colleagues for helpful discussions. We thank H. Teunissen, T. van den Brand and M. Panarotto-Périclès for technical assistance, K. Shirahige (The University of Tokyo) for the acetylated SMC3 antibody, S. Rankin (Oklahoma Medical Research Foundation) for the ESCO1 antibody, T. Perrakis for advice on protein structure, M. Vermeulen and I. Santos-Barriopedro for experiments not included in the manuscript and the NKI Genomics Core facility and Flow Cytometry facility for assistance. M.S.v.R. was supported by Boehringer Ingelheim Fonds; M.S.v.R., D.G., Á.S.C. and B.D.R. by the European Research Council (no. ERC 772471—‘CohesinLooping’); J.H.I.H. and L.W. by the Dutch Cancer Society (no. KWF 11665); L.H. and M.A. by the Dutch NWO X-omics Initiative (no. 184.034.019); E.d.W. by the European Research Council (nos. ERC 637587—‘HAP-PHEN’ and ERC 865459—‘FuncDis3D’); and T.R.B. by the Dutch Research Council (no. 016.Vici.170.033). Publisher Copyright: © 2022, The Author(s).
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