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Nat Immunol. 2010 Mar;11(3):207-15. doi: 10.1038/ni.1839. Epub 2010 Jan 17.

Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase-substrate complex.

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1
Howard Hughes Medical Institute and Department of Pathology, New York, New York, USA.

Abstract

Hematopoietic stem cell (HSC) differentiation is regulated by cell-intrinsic and cell-extrinsic cues. In addition to transcriptional regulation, post-translational regulation may also control HSC differentiation. To test this hypothesis, we visualized the ubiquitin-regulated protein stability of a single transcription factor, c-Myc. The stability of c-Myc protein was indicative of HSC quiescence, and c-Myc protein abundance was controlled by the ubiquitin ligase Fbw7. Fine changes in the stability of c-Myc protein regulated the HSC gene-expression signature. Using whole-genome genomic approaches, we identified specific regulators of HSC function directly controlled by c-Myc binding; however, adult HSCs and embryonic stem cells sensed and interpreted c-Myc-regulated gene expression in distinct ways. Our studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentiation.

PMID:
20081848
PMCID:
PMC2825759
DOI:
10.1038/ni.1839
[Indexed for MEDLINE]
Free PMC Article
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