ETO2 coordinates cellular proliferation and differentiation during erythropoiesis

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-loophelix 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 erythroidspecific 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.

Adenoviral E1B55K oncoprotein sequesters candidate leukemia suppressor sequence-specific single-stranded DNA-binding protein 2 into aggresomes

“…We also examined the localization of the related family protein SSBP3 in 293 cells (Figure 1c). The SSBP3 protein shares 83% identity to SSBP2 and is also found in Ldb1 containing transcriptional complexes (Goardon et al, 2006;Liang and Nagarajan, unpublished data). Although very similar to SSBP2, this protein appeared to be predominantly nuclear and did not reside in cytoplasmic structures in 293 cells.…”

“…Physical interaction with Ldb1 allows SSBP to modulate activity of LIM-homeodomain genes and LIM-only genes in a differentiation pathway that is conserved in Drosophila, Xenopus and mice (Chen et al, 2002;van Meyel et al, 2003;Nishioka et al, 2005). Recent evidence suggests that SSBP2 may be part of a stem cell leukemia factor (SCL), Ldb1-containing multi-protein complex required for erythroid differentiation (Schuh et al, 2005;Goardon et al, 2006). In addition to regulating activity of transcription factors, SSBP proteins may also have inherent transcriptional activity (Wu, 2006).…”

MTB, the murine homolog of condensin II subunit CAP-G2, represses transcription and promotes erythroid cell differentiation

“…13 More recently, it has been shown that SCL/E2A interacts with ETO-2 to form a repression complex in proerythroblasts. 14,15 Thus, SCL appears to function both as an activator and repressor, dependent on its cellular context. MTB is the murine homolog of FLJ20311, which has been identified as one of the condensin II complex subunits hCAP-G2.…”

Mtg16/Eto2 Contributes to Murine T-Cell Development

“…These translocations fuse the DNA-binding domain of RUNX1 to nearly all of either MTG16 or MTG8 to repress the transcription of RUNX1-regulated genes (15,17,18,33). As expected for corepressors, MTG16 binds to both DNA binding proteins and chromatin-modifying factors (1,9,14,19,34,41). Four highly homologous domains within MTGs are evolutionarily conserved in the Drosophila melanogaster factor Nervy and mediate some of these contacts.…”

“…The action of E proteins and Notch signaling are critical to T-cell development, and a potential role for Mtg16 in lymphopoiesis was further suggested by the identification of an association between MTGs and these pathways (9,14,19,38,41,48). Upon ligand binding, the Notch receptor is cleaved and the intracellular domain (ICD) of Notch moves to the nucleus and binds the transcription factor CBF1-Suppressor of Hairless-Lag1 (CSL) to activate transcription (26).…”