NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal.
Hematopoietic stem cell (HSC) self-renewal and differentiation are influenced through multiple pathways, including homeobox transcription factors, signaling through beta-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.
Zhu
Jiang
J
Department of Medicine, and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Zhang
Yi
Y
Joe
Gerard J
GJ
Pompetti
Richard
R
Emerson
Stephen G
SG
D000818:Animals; D023081:CCAAT-Binding Factor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D012038:Regeneration; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D023081:CCAAT-Binding Factor; D018398:Homeodomain Proteins; C513262:Hoxb4 protein, mouse; C492061:NFYA protein, human; D014157:Transcription Factors