Maturation stage-specific regulation of megakaryopoiesis by pointed-domain Ets proteins.
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.
Pang
Liyan
L
Children's Hospital of Philadelphia, ARC 316H, 3165 Civic Center Blvd, Philadelphia, PA, USA.
Xue
Hai-Hui
HH
Szalai
Gabor
G
Wang
Xun
X
Wang
Yuhuan
Y
Watson
Dennis K
DK
Leonard
Warren J
WJ
Blobel
Gerd A
GA
Poncz
Mortimer
M
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
C497426:Fli1 protein, mouse; D050784:Proto-Oncogene Protein c-ets-1; D051789:Proto-Oncogene Protein c-fli-1