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Nat Commun. 2015 Nov 23;6:8893. doi: 10.1038/ncomms9893.

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

Author information

1
Department of Cell Biology, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
2
Inserm UMR967, CEA/DSV/iRCM, Laboratory of Molecular Hematopoiesis, Université Paris-Saclay, 92265 Fontenay-aux-Roses, France.
3
Computational Biology Unit, Bergen Center for Computational Science, N-5008 Bergen, Norway.
4
MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
5
Department of Proteomics, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
6
CEA/DSV/iRCM/SCSR, Université Paris-Saclay, 92265 Fontenay-aux-Roses, France.
7
Center for Biomics, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
8
Inserm UMR967, CEA/DSV/iRCM, Laboratory of Hematopoietic and Leukemic Stem cells, Université Paris-Saclay, 92265 Fontenay-aux-Roses, France.
9
Department of Molecular Sciences, Faculty of Medicine, MRC Clinical Sciences Centre, Institute of Clinical Sciences, Imperial College London, London W12 0NN, UK.
10
Cancer Genomics Center, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
11
Laboratory of Excellence GR-Ex, 75015 Paris, France.

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.

PMID:
26593974
PMCID:
PMC4673834
DOI:
10.1038/ncomms9893
[Indexed for MEDLINE]
Free PMC Article

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