Control of developmentally primed erythroid genes by combinatorial co-repressor actions

Ralph Stadhouders (), Alba Cico, Tharshana Stephen, Supat Thongjuea, Petros Kolovos, H. Irem Baymaz, Xiao Yu, Jeroen Demmers, Karel Bezstarosti, Alex Maas, Vilma Barroca, Christel Kockx, Zeliha Ozgur, Wilfred van Ijcken, Marie-Laure Arcangeli, Charlotte Andrieu-Soler, Boris Lenhard, Frank Grosveld and Eric Soler ()
Additional contact information
Ralph Stadhouders: Erasmus Medical Center
Alba Cico: Inserm UMR967, CEA/DSV/iRCM, Laboratory of Molecular Hematopoiesis, Université Paris-Saclay
Tharshana Stephen: Inserm UMR967, CEA/DSV/iRCM, Laboratory of Molecular Hematopoiesis, Université Paris-Saclay
Supat Thongjuea: Computational Biology Unit, Bergen Center for Computational Science
Petros Kolovos: Erasmus Medical Center
H. Irem Baymaz: Erasmus Medical Center
Xiao Yu: Erasmus Medical Center
Jeroen Demmers: Erasmus Medical Center
Karel Bezstarosti: Erasmus Medical Center
Alex Maas: Erasmus Medical Center
Vilma Barroca: CEA/DSV/iRCM/SCSR, Université Paris-Saclay
Christel Kockx: Center for Biomics, Erasmus Medical Center
Zeliha Ozgur: Center for Biomics, Erasmus Medical Center
Wilfred van Ijcken: Center for Biomics, Erasmus Medical Center
Marie-Laure Arcangeli: Inserm UMR967, CEA/DSV/iRCM, Laboratory of Hematopoietic and Leukemic Stem cells, Université Paris-Saclay
Charlotte Andrieu-Soler: Inserm UMR967, CEA/DSV/iRCM, Laboratory of Molecular Hematopoiesis, Université Paris-Saclay
Boris Lenhard: Faculty of Medicine, MRC Clinical Sciences Centre, Institute of Clinical Sciences, Imperial College London
Frank Grosveld: Erasmus Medical Center
Eric Soler: Erasmus Medical Center

Nature Communications, 2015, vol. 6, issue 1, 1-17

Abstract: Abstract How transcription factors (TFs) cooperate within large protein complexes to allow rapid modulation of gene expression during development is still largely unknown. Here we show that the key haematopoietic LIM-domain-binding protein-1 (LDB1) TF complex contains several activator and repressor components that together maintain an erythroid-specific gene expression programme primed for rapid activation until differentiation is induced. A combination of proteomics, functional genomics and in vivo studies presented here identifies known and novel co-repressors, most notably the ETO2 and IRF2BP2 proteins, involved in maintaining this primed state. The ETO2–IRF2BP2 axis, interacting with the NCOR1/SMRT co-repressor complex, suppresses the expression of the vast majority of archetypical erythroid genes and pathways until its decommissioning at the onset of terminal erythroid differentiation. Our experiments demonstrate that multimeric regulatory complexes feature a dynamic interplay between activating and repressing components that determines lineage-specific gene expression and cellular differentiation.

Date: 2015
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DOI: 10.1038/ncomms9893

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