Cohesin depleted cells rebuild functional nuclear compartments after endomitosis
Marion Cremer, Katharina Brandstetter, Andreas Maiser, Suhas S.P. Rao, Volker Schmid, Miguel Guirao‐Ortiz, Namita Mitra, Stefania Mamberti, Kyle N. Klein, David M. Gilbert, Heinrich Leonhardt, M. Cristina Cardoso, Erez Lieberman Aiden, Hartmann Harz, Thomas Cremer
Abstract
Cohesin plays an essential role in chromatin loop extrusion, but its impact on a compartmentalized nuclear architecture, linked to nuclear functions, is less well understood. Using live-cell and super-resolved 3D microscopy, here we find that cohesin depletion in a human colon cancer derived cell line results in endomitosis and a single multilobulated nucleus with chromosome territories pervaded by interchromatin channels. Chromosome territories contain chromatin domain clusters with a zonal organization of repressed chromatin domains in the interior and transcriptionally competent domains located at the periphery. These clusters form microscopically defined, active and inactive compartments, which likely correspond to A/B compartments, which are detected with ensemble Hi-C. Splicing speckles are observed nearby within the lining channel system. We further observe that the multilobulated nuclei, despite continuous absence of cohesin, pass through S-phase with typical spatio-temporal patterns of replication domains. Evidence for structural changes of these domains compared to controls suggests that cohesin is required for their full integrity.