Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 33, Pages 11728-11733Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0503405102
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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.
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