NFI-A directs the fate of hematopoietic progenitors to the erythroid or granulocytic lineage and controls β-globin and G-CSF receptor expression
- Linda Marie Starnes1,2,*,
- Antonio Sorrentino3,*,
- Elvira Pelosi3,
- Monica Ballarino4,
- Ornella Morsilli3,
- Mauro Biffoni3,
- Simona Santoro3,
- Nadia Felli3,
- Germana Castelli3,
- Maria Laura De Marchis4,
- Gianfranco Mastroberardino5,
- Marco Gabbianelli3,
- Alessandro Fatica4,
- Irene Bozzoni4,
- Clara Nervi1,2, and
- Cesare Peschle6
- 1Department of Histology and Medical Embryology, University “La Sapienza,” Rome;
- 2San Raffaele Biomedical Park Foundation, Rome;
- 3Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome;
- Departments of 4Genetics and Molecular Biology and Istituto di Biologia e Patologia Molecolari (IBPM) and
- 5Medicine, University “La Sapienza,” Rome; and
- 6Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) MultiMedica, Milan, Italy
Abstract
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 β-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.
- Submitted December 22, 2008.
- Accepted May 14, 2009.
- Final version accepted March 31, 2009.
- © 2009 by The American Society of Hematology
