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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.

Original publication

DOI

10.1038/ncomms9893

Type

Journal article

Journal

Nat Commun

Publication Date

23/11/2015

Volume

6

Keywords

Amino Acid Sequence, Animals, Base Sequence, Carrier Proteins, DNA-Binding Proteins, Erythroid Cells, Erythropoiesis, Gene Expression Regulation, Developmental, Humans, LIM Domain Proteins, Mice, Molecular Sequence Data, Nuclear Proteins, Nuclear Receptor Co-Repressor 1, Nuclear Receptor Co-Repressor 2, Repressor Proteins, Transcription Factors, Tumor Suppressor Proteins