NFI-A directs the fate of hematopoietic progenitors to the erythroid or granulocytic lineage and controls beta-globin and G-CSF receptor expression.
It is generally conceded that selective combinations of transcription factors determine hematopoietic lineage commitment and differentiation. Here we show that in normal human hematopoiesis the transcription factor nuclear factor I-A (NFI-A) exhibits a marked lineage-specific expression pattern: it is upmodulated in the erythroid (E) lineage while fully suppressed in the granulopoietic (G) series. In unilineage E culture of hematopoietic progenitor cells (HPCs), NFI-A overexpression or knockdown accelerates or blocks erythropoiesis, respectively: notably, NFI-A overexpression restores E differentiation in the presence of low or minimal erythropoietin stimulus. Conversely, NFI-A ectopic expression in unilineage G culture induces a sharp inhibition of granulopoiesis. Finally, in bilineage E + G culture, NFI-A overexpression or suppression drives HPCs into the E or G differentiation pathways, respectively. These NFI-A actions are mediated, at least in part, by a dual and opposite transcriptional action: direct binding and activation or repression of the promoters of the beta-globin and G-CSF receptor gene, respectively. Altogether, these results indicate that, in early hematopoiesis, the NFI-A expression level acts as a novel factor channeling HPCs into either the E or G lineage.
Starnes
Linda Marie
LM
Department of Histology and Medical Embryology, University La Sapienza, Rome, Italy.
Sorrentino
Antonio
A
Pelosi
Elvira
E
Ballarino
Monica
M
Morsilli
Ornella
O
Biffoni
Mauro
M
Santoro
Simona
S
Felli
Nadia
N
Castelli
Germana
G
De Marchis
Maria Laura
ML
Mastroberardino
Gianfranco
G
Gabbianelli
Marco
M
Fatica
Alessandro
A
Bozzoni
Irene
I
Nervi
Clara
C
Peschle
Cesare
C
D018952:Antigens, CD34 / Q000096:biosynthesis; D002454:Cell Differentiation; D019070:Cell Lineage; D004912:Erythrocytes / Q000378:metabolism*; D004921:Erythropoietin / Q000378:metabolism; D005312:Fetal Blood / Q000378:metabolism; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D008954:Models, Biological; D051839:NFI Transcription Factors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000378:metabolism*; D055544:beta-Globins / Q000378:metabolism*
D018952:Antigens, CD34; D051839:NFI Transcription Factors; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D055544:beta-Globins; D004921:Erythropoietin