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

Linsey Reavie, Giusy Della Gatta, Kelly Crusio, Beatriz Aranda-Orgilles, Shannon M. Buckley, Benjamin Thompson, Eugine Lee, Jie Gao, Andrea L. Bredemeyer, Beth A. Helmink, Jiri Zavadil, Barry P. Sleckman, Teresa Palomero, Adolfo Ferrando, Iannis Aifantis

Research output: Contribution to journalArticle

77 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)207-215
Number of pages9
JournalNature Immunology
Volume11
Issue number3
DOIs
StatePublished - Mar 2010

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Reavie, L., Gatta, G. D., Crusio, K., Aranda-Orgilles, B., Buckley, S. M., Thompson, B., Lee, E., Gao, J., Bredemeyer, A. L., Helmink, B. A., Zavadil, J., Sleckman, B. P., Palomero, T., Ferrando, A., & Aifantis, I. (2010). Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase-substrate complex. Nature Immunology, 11(3), 207-215. https://doi.org/10.1038/ni.1839