NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal

doi:10.1073/pnas.0503405102

NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal

Departments of Medicine and Pediatrics, and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Communicated by Zhu Chen, Shanghai Second Medical University, Shanghai, People's Republic of China, April 25, 2005 (received for review December 15, 2004)

Abstract

Hematopoietic stem cell (HSC) self-renewal and differentiation are influenced through multiple pathways, including homeobox transcription factors, signaling through β-catenin and Notch-1, telomerase, and p27. How these multiple pathways interact and are orchestrated is currently unknown. We now report that NF-Ya, the regulatory and DNA-binding subunit of the trimeric transcription factor NF-Y, plays a central, integrating role in several of these HSC pathways. NF-Ya is preferentially expressed in HSC-enriched bone marrow subpopulations, and NF-Ya mRNA rapidly declines with HSC differentiation. Overexpression of NF-Ya in primitive hematopoietic cells activates the transcription of multiple HOX4 paralogs, as well as Notch-1, LEF-1, and telomerase RNA. HSCs overexpressing NF-Ya are biased toward primitive hematopoiesis in vitro and show strikingly increased in vivo repopulating abilities after single or sequential bone marrow transplantation. Thus, NF-Ya is a potent cellular regulator of HSC self-renewal.

Footnotes

↵ * To whom correspondence should be addressed at: Division of Hematology/Oncology, University of Pennsylvania School of Medicine, Maloney 510, 3600 Spruce Street, Philadelphia, PA 19104. E-mail: emersons{at}mail.med.upenn.edu.
Author contributions: J.Z. and S.G.E. designed research; J.Z., Y.Z., G.J.J., and R.P. performed research; J.Z. contributed new reagents/analytic tools; J.Z., Y.Z., G.J.J., and S.G.E. analyzed data; and J.Z. and S.G.E. wrote the paper.
Abbreviations: BM, bone marrow; BMT, bone marrow transplantation; ChIP, chromatin immunoprecipitation; CRU, competitive repopulating units; HSC, hematopoietic stem cell; SC, stem cell; SCF, stem cell factor.