Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase-substrate complex.
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.
Reavie
Linsey
L
Howard Hughes Medical Institute and Department of Pathology, New York, New York, USA.
Della Gatta
Giusy
G
Crusio
Kelly
K
Aranda-Orgilles
Beatriz
B
Buckley
Shannon M
SM
Thompson
Benjamin
B
Lee
Eugine
E
Gao
Jie
J
Bredemeyer
Andrea L
AL
Helmink
Beth A
BA
Zavadil
Jiri
J
Sleckman
Barry P
BP
Palomero
Teresa
T
Ferrando
Adolfo
A
Aifantis
Iannis
I
D000818:Animals; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D018797:Cell Cycle Proteins / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016271:Proto-Oncogene Proteins c-myc / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000276:immunology*
D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc; D044767:Ubiquitin-Protein Ligases