CEBPA phase separation links transcriptional activity and 3D chromatin hubs

Christou-Kent, Marie; Cuartero, Sergi; Garcia-Cabau, Carla; Ruehle, Julia; Naderi, Julian; Erber, Julia; Neguembor, Maria Victoria; Plana Carmona, Marcos, 1993-; Alcoverro-Bertran, Marc; Andrés Aguayo, Luisa de; Klonizakis, Antonios; Julià Vilella, Eric; Lynch, Cian J.; Serrano, Manuel; Hnisz, Denes; Salvatella, Xavier; Graf, T. (Thomas); Stik, Grégoire

doi:http://dx.doi.org/10.1016/j.celrep.2023.112897

CEBPA phase separation links transcriptional activity and 3D chromatin hubs

Citation

Christou-Kent M, Cuartero S, Garcia-Cabau C, Ruehle J, Naderi J, Erber J, Neguembor MV, Plana-Carmona M, Alcoverro-Bertran M, De Andres-Aguayo L, Klonizakis A, Julià-Vilella E, Lynch C, Serrano M, Hnisz D, Salvatella X, Graf T, Stik G. CEBPA phase separation links transcriptional activity and 3D chromatin hubs. Cell Rep. 2023 Aug 29;42(8):112897. DOI: 10.1016/j.celrep.2023.112897

Abstract

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.