Departement d'Hematologie, Institut Cochin, INSERM U567, CNRS UMR 8104, Universite Paris V, Paris, France-
Abstract: The passage from proliferation to terminal differentiation is critical for normal development and is often perturbed in malignancies- To define the molecular mechanisms that govern this process during erythropoiesis, we have used tagging-proteomics approaches and characterized protein complexes nucleated by TAL-1-SCL, a basic helix-loop-helix transcription factor that specifies the erythrocytic lineage- In addition to known TAL-1 partners, GATA-1, E2A, HEB, LMO2 and Ldb1, we identify the ETO2 repressor as a novel component recruited to TAL-1 complexes through interaction with E2A-HEB- Ectopic expression and siRNA knockdown experiments in hematopoietic progenitor cells show that ETO2 actively represses erythroid TAL-1 target genes and governs the expansion of erythroid progenitors- At the onset of erythroid differentiation, a change in the stoichiometry of ETO2 within the TAL-1 complex activates the expression of known erythroid-specific TAL-1 target genes and of Gfi-1b and p21-Cip-, encoding two essential regulators of erythroid cell proliferation- These results suggest that the dynamics of ETO2 recruitment within nuclear complexes couple cell proliferation to cell differentiation and determine the onset of terminal erythroid maturation-