CEBPA phase separation links transcriptional activity and 3D chromatin hubs
Marie Christou-Kent,
Sergi Cuartero,
Carla Garcia-Cabau,
Julia Ruehle,
Julian Naderi,
Julia Erber,
Maria Victoria Neguembor,
Marcos Plana-Carmona,
Marc Alcoverro-Bertran,
Luisa De Andres-Aguayo,
Antonios Klonizakis,
Eric Julià-Vilella,
Cian Lynch,
Manuel Serrano,
Denes Hnisz,
Xavier Salvatella,
Thomas Graf,
Grégoire Stik
Affiliations
Marie Christou-Kent
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain
Sergi Cuartero
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain; Germans Trias I Pujol Research Institute (IGTP), Badalona, Spain
Carla Garcia-Cabau
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain
Julia Ruehle
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain
Julian Naderi
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany
Julia Erber
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain
Maria Victoria Neguembor
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain
Marcos Plana-Carmona
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain
Marc Alcoverro-Bertran
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain
Luisa De Andres-Aguayo
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain
Antonios Klonizakis
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain
Eric Julià-Vilella
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain
Cian Lynch
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; Altos Labs, Cambridge Institute of Science, Cambridge CB21 6GP, UK
Manuel Serrano
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; Altos Labs, Cambridge Institute of Science, Cambridge CB21 6GP, UK
Denes Hnisz
Department of Genome Regulation, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany
Xavier Salvatella
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028 Barcelona, Spain; ICREA, Passeig Lluís Companys 23, 08010 Barcelona, Spain
Thomas Graf
Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain; Corresponding author
Grégoire Stik
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Spain; Corresponding author
Summary: Cell identity is orchestrated through an interplay between transcription factor (TF) action and genome architecture. The mechanisms used by TFs to shape three-dimensional (3D) genome organization remain incompletely understood. Here we present evidence that the lineage-instructive TF CEBPA drives extensive chromatin compartment switching and promotes the formation of long-range chromatin hubs during induced B cell-to-macrophage transdifferentiation. Mechanistically, we find that the intrinsically disordered region (IDR) of CEBPA undergoes in vitro phase separation (PS) dependent on aromatic residues. Both overexpressing B cells and native CEBPA-expressing cell types such as primary granulocyte-macrophage progenitors, liver cells, and trophectoderm cells reveal nuclear CEBPA foci and long-range 3D chromatin hubs at CEBPA-bound regions. In short, we show that CEBPA can undergo PS through its IDR, which may underlie in vivo foci formation and suggest a potential role of PS in regulating CEBPA function.
