title: Control of developmentally primed erythroid genes by combinatorial co-repressor actions.
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.
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Ralph
authors.initials: R
authors.lastname: Stadhouders
authors.affiliation: Inserm UMR967, CEA/DSV/iRCM, Laboratory of Molecular Hematopoiesis, Université Paris-Saclay, 92265 Fontenay-aux-Roses, France.
authors.forename: Alba
authors.initials: A
authors.lastname: Cico
authors.affiliation: Inserm UMR967, CEA/DSV/iRCM, Laboratory of Molecular Hematopoiesis, Université Paris-Saclay, 92265 Fontenay-aux-Roses, France.
authors.forename: Tharshana
authors.initials: T
authors.lastname: Stephen
authors.affiliation: Computational Biology Unit, Bergen Center for Computational Science, N-5008 Bergen, Norway.|MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Supat
authors.initials: S
authors.lastname: Thongjuea
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Petros
authors.initials: P
authors.lastname: Kolovos
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: H Irem
authors.initials: HI
authors.lastname: Baymaz
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Proteomics, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Demmers
authors.affiliation: Department of Proteomics, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Karel
authors.initials: K
authors.lastname: Bezstarosti
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Alex
authors.initials: A
authors.lastname: Maas
authors.affiliation: CEA/DSV/iRCM/SCSR, Université Paris-Saclay, 92265 Fontenay-aux-Roses, France.
authors.forename: Vilma
authors.initials: V
authors.lastname: Barroca
authors.affiliation: Center for Biomics, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Christel
authors.initials: C
authors.lastname: Kockx
authors.affiliation: Center for Biomics, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Zeliha
authors.initials: Z
authors.lastname: Ozgur
authors.affiliation: Center for Biomics, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Wilfred
authors.identifier: http://orcid.org/0000-0002-0421-8301
authors.initials: W
authors.lastname: van Ijcken
authors.affiliation: Inserm UMR967, CEA/DSV/iRCM, Laboratory of Hematopoietic and Leukemic Stem cells, Université Paris-Saclay, 92265 Fontenay-aux-Roses, France.
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Arcangeli
authors.affiliation: Inserm UMR967, CEA/DSV/iRCM, Laboratory of Molecular Hematopoiesis, Université Paris-Saclay, 92265 Fontenay-aux-Roses, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Andrieu-Soler
authors.affiliation: Department of Molecular Sciences, Faculty of Medicine, MRC Clinical Sciences Centre, Institute of Clinical Sciences, Imperial College London, London W12 0NN, UK.
authors.forename: Boris
authors.identifier: http://orcid.org/0000-0002-1114-1509
authors.initials: B
authors.lastname: Lenhard
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.|Cancer Genomics Center, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.
authors.forename: Frank
authors.initials: F
authors.lastname: Grosveld
authors.affiliation: Department of Cell Biology, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.|Inserm UMR967, CEA/DSV/iRCM, Laboratory of Molecular Hematopoiesis, Université Paris-Saclay, 92265 Fontenay-aux-Roses, France.|Cancer Genomics Center, Erasmus Medical Center, 3015CN Rotterdam, The Netherlands.|Laboratory of Excellence GR-Ex, 75015 Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Soler
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D004920:Erythropoiesis; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1 / Q000235:genetics / Q000378:metabolism; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C115744:CBFA2T3 protein, human; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C475082:IRF2BP2 protein, human; C486312:LDB1 protein, human; D060588:LIM Domain Proteins; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D012097:Repressor Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins