title: Regulation of hematopoietic stem cell differentiation by a single ubiquitin ligase-substrate complex.
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.
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, New York, New York, USA.
authors.forename: Linsey
authors.initials: L
authors.lastname: Reavie
authors.forename: Giusy
authors.initials: G
authors.lastname: Della Gatta
authors.forename: Kelly
authors.initials: K
authors.lastname: Crusio
authors.forename: Beatriz
authors.initials: B
authors.lastname: Aranda-Orgilles
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Buckley
authors.forename: Benjamin
authors.initials: B
authors.lastname: Thompson
authors.forename: Eugine
authors.initials: E
authors.lastname: Lee
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Bredemeyer
authors.forename: Beth A
authors.initials: BA
authors.lastname: Helmink
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
authors.forename: Adolfo
authors.initials: A
authors.lastname: Ferrando
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
mesh_terms: 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*
chemical_list: D018797:Cell Cycle Proteins; D016271:Proto-Oncogene Proteins c-myc; D044767:Ubiquitin-Protein Ligases