Journal
NATURE IMMUNOLOGY
Volume 11, Issue 3, Pages 207-U3Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.1839
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Funding
- National Institutes of Health [RO1CA133379, RO1CA105129, R21CA141399, R56AI070310, P30CA016087, RO1AI41428, RO1AI072039, R01CA120196]
- American Cancer Society [RSG0806801]
- Edward Mallinckrodt Jr. Foundation
- Irma T. Hirschl Trust
- Alex's Lemonade Stand Foundation
- Alexander von Humboldt Foundation
- NYU Hematology/Oncology Program
- NYU Molecular Oncology and Immunology Training [5T32CA009161]
- Leukemia & Lymphoma Society
- Howard Hughes Medical Institute
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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.
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