Article
- The EMBO Journal (2006) 25, 357 - 366
- doi:10.1038/sj.emboj.7600934
Published online: 12 January 2006
Subject Categories:
ETO2 coordinates cellular proliferation and differentiation during erythropoiesis
Nicolas Goardon1,4, Julie A Lambert2,4, Patrick Rodriguez3, Philippe Nissaire2, Sabine Herblot2, Pierre Thibault2, Dominique Dumenil1, John Strouboulis3, Paul-Henri Romeo1,4 and Trang Hoang2,4
- Département d'Hématologie, Institut Cochin, INSERM U567, CNRS UMR 8104, Université Paris V, Paris, France
- Institute of Research in Immunology and Cancer (IRIC)—Pharmacology, Chemistry, Biochemistry and Molecular Biology Departments, University of Montreal, Montréal, Québec, Canada
- Department of Cell Biology, Erasmus University Medical Center, Rotterdam, The Netherlands
- These authors contributed equally to this work
Correspondence to:
Paul-Henri Romeo, Département d'Hématologie, Institut Cochin, INSERM U567, CNRS UMR 8104, Université Paris V, Paris 75014, France. Tel.: +33 1 53 10 43 51; Fax: +33 1 43 25 11 67; E-mail: romeo@cochin.inserm.fr
Trang Hoang, Institute of Research in Immunology and Cancer (IRIC)—Pharmacology, Chemistry, Biochemistry and Molecular Biology Departments, University of Montreal, Montréal, Québec, Canada H3C 3J7. Tel.: +1 514 343 6970; Fax: +1 343 6945; E-mail: trang.hoang@umontreal.ca
Received 27 July 2005; Accepted 2 December 2005
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 p21Cip, 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.
Keywords:
- differentiation,
- erythropoiesis,
- ETO2,
- hematopoiesis,
- proliferation,
- TAL-1
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