title: Maturation stage-specific regulation of megakaryopoiesis by pointed-domain Ets proteins.
abstract: Numerous megakaryocyte-specific genes contain signature Ets-binding sites in their regulatory regions. Fli-1 (friend leukemia integration 1), an Ets transcription factor, is required for the normal maturation of megakaryocytes and controls the expression of multiple megakaryocyte-specific genes. However, in Fli-1-/- mice, early megakaryopoiesis persists, and the expression of the early megakaryocyte-specific genes, alphaIIb and cMpl, is maintained, consistent with functional compensation by a related Ets factor(s). Here we identify the Ets protein GABPalpha (GA-binding protein alpha) as a regulator of early megakaryocyte-specific genes. Notably, GABPalpha preferentially occupies Ets elements of early megakaryocyte-specific genes in vitro and in vivo, whereas Fli-1 binds both early and late megakaryocyte-specific genes. Moreover, the ratio of GABPalpha/Fli-1 expression declines throughout megakaryocyte maturation. Consistent with this expression pattern, primary fetal liver-derived megakaryocytes from Fli-1-deficient murine embryos exhibit reduced expression of genes associated with late stages of maturation (glycoprotein [GP] Ibalpha, GPIX, and platelet factor 4 [PF4]), whereas GABPalpha-deficient megakaryocytes were mostly impaired in the expression of early megakaryocyte-specific genes (alphaIIb and cMpl). Finally, mechanistic experiments revealed that GABPalpha, like Fli-1, can impart transcriptional synergy between the hematopoietic transcription factor GATA-1 and its cofactor FOG-1 (friend of GATA-1). In concert, these data reveal disparate, but overlapping, functions of Ets transcription factors at distinct stages of megakaryocyte maturation.
authors.affiliation: Children's Hospital of Philadelphia, ARC 316H, 3165 Civic Center Blvd, Philadelphia, PA, USA.
authors.forename: Liyan
authors.initials: L
authors.lastname: Pang
authors.forename: Hai-Hui
authors.initials: HH
authors.lastname: Xue
authors.forename: Gabor
authors.initials: G
authors.lastname: Szalai
authors.forename: Xun
authors.initials: X
authors.lastname: Wang
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Watson
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Blobel
authors.forename: Mortimer
authors.initials: M
authors.lastname: Poncz
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D008099:Liver / Q000196:embryology; D008533:Megakaryocytes / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D050784:Proto-Oncogene Protein c-ets-1 / Q000737:chemistry*; D051789:Proto-Oncogene Protein c-fli-1 / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C497426:Fli1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D051789:Proto-Oncogene Protein c-fli-1