CEBPA phase separation links transcriptional activity and 3D chromatin hubs
Christou-Kent, Marie (Centre for Genomic Regulation (CRG). The Barcelona Institute of Science and Technology)
Cuartero, Sergi (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Garcia-Cabau, Carla (Institute for Research in Biomedicine (IRB Barcelona))
Ruehle, Julia (Centre for Genomic Regulation (CRG). The Barcelona Institute of Science and Technology)
Naderi, Julian (Department of Genome Regulation. Max Planck Institute for Molecular Genetics)
Erber, Julia (Centre for Genomic Regulation (CRG). The Barcelona Institute of Science and Technology)
Neguembor, Maria Victoria (Centre for Genomic Regulation (CRG). The Barcelona Institute of Science and Technology)
Plana-Carmona, Marcos (Centre for Genomic Regulation (CRG). The Barcelona Institute of Science and Technology)
Alcoverro Bertran, Marc (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
de Andrés-Aguayo, Luisa (Centre de Regulació Genòmica)
Klonizakis, Antonios (Centre for Genomic Regulation (CRG). The Barcelona Institute of Science and Technology)
Julià Vilella, Eric (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Lynch, Cian (Altos Labs. Cambridge Institute of Science)
Serrano, Manuel (Altos Labs. Cambridge Institute of Science)
Hnisz, Denes (Department of Genome Regulation. Max Planck Institute for Molecular Genetics)
Salvatella, Xavier (Institució Catalana de Recerca i Estudis Avançats)
Graf, Thomas (Universitat Pompeu Fabra)
Stik, Grégoire (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)

Fecha:	2023
Resumen:	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.
Ayudas:	Agència de Gestió d'Ajuts Universitaris i de Recerca 2017 SGR 324 Agència de Gestió d'Ajuts Universitaris i de Recerca BIO2015-70092-R Agència de Gestió d'Ajuts Universitaris i de Recerca PID2019-110198RB-I00 Ministerio de Economía y Competitividad PRE2018-084684 Ministerio de Ciencia e Innovación PCI2021-122032-2B Ministerio de Ciencia e Innovación PID2020-117950RA-I00
Nota:	We thank the Graf lab members for helpful discussions, and the CRG Genomics, Flow Cytometry and Advanced Light Microscopy core facilities; M.C.-K. was supported by an EMBO postdoctoral fellowship (ALTF 1057-2019) and PCIN-MSCA-fellowship (Ministerio de Ciencia e Innovación PCI2021-122032-2B). S.C. is supported by a "La Caixa" Junior Leader fellowship, by the Jérôme Lejeune Foundation (JLF#1902) and the Spanish Ministry of Science and Innovation (PID2020-117950RA-I00). G.S. was supported by the "Fundación Científica de la Asociación Española Contra el Cáncer. " M.V.N. was supported by People Program (Marie Curie Actions) FP7/2007-2013 under REA grant 6089 and Juan de la Cierva-Incorporación 2017. C.G.-C. acknowledges a graduate fellowship from MINECO (PRE2018-084684). X.S. acknowledges funding from AGAUR (2017 SGR 324), MINECO (BIO2015-70092-R and PID2019-110198RB-I00), and the European Research Council (CONCERT, contract number 648201). This work was funded by the Max Planck Society and partially supported by grants from the Deutsche Forschungsgemeinschaft (DFG) SPP2202 Priority Program Grant HN 4/1-1 (to D.H.) and by the Spanish Ministry of Economy, Industry and Competitiveness (MEIC) Plan Estatal 2015, SAF.2015-68740-P (to T.G.). We acknowledge support by the Spanish Ministry of Science and Innovation, to the EMBL partnership, the Centro de Excelencia Severo Ochoa, the Josep Carreras Foundation, and the CERCA Programme / Generalitat de Catalunya.
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	CEBPA ; Condensates ; Phase separation ; Transcription ; Chromatin hubs ; Transdifferentiation ; Gene regulation ; 3D genome organization ; Compartments
Publicado en:	Cell reports, Vol. 42 Núm. 8 (29 2023) , p. 112897, ISSN 2211-1247

DOI: 10.1016/j.celrep.2023.112897

33 p, 8.1 MB

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