@article{458fadaa84a34c80881f92d7e1ca1568,
title = "Bmi1 suppresses protein synthesis and promotes proteostasis in hematopoietic stem cells",
abstract = "The polycomb complex component Bmi1 promotes the maintenance of stem cells in multiple postnatal tissues, partly by negatively regulating the expression of p16Ink4a and p19Arf, tumor suppressors associated with cellular senescence. However, deficiency for p16Ink4a and p19Arf only partially rescues the function of Bmi1-deficient stem cells. We conditionally deleted Bmi1 from adult hematopoietic cells and found that this slowly depleted hematopoietic stem cells (HSCs). Rather than inducing senescence, Bmi1 deficiency increased HSC division. The increased cell division was caused partly by increased Aristaless-related homeobox (ARX) transcription factor expression, which also increased ribosomal RNA expression. However, ARX deficiency did not rescue HSC depletion. Bmi1 deficiency also increased protein synthesis, protein aggregation, and protein ubiquitylation independent of its effects on cell division and p16Ink4a, p19Arf, and ARX expression. Bmi1 thus promotes HSC quiescence by negatively regulating ARX expression and promotes proteostasis by suppressing protein synthesis. This highlights a new connection between the regulation of stem cell maintenance and proteostasis.",
keywords = "polycomb, self-renewal, senescence, tissue regeneration, tumor suppressor",
author = "Burgess, {Rebecca J.} and Zhiyu Zhao and Daisuke Nakada and Morrison, {Sean J.}",
note = "Funding Information: S.J.M. is a Howard Hughes Medical Institute (HHMI) Investigator, the Mary McDermott Cook Chair in Pediatric Genetics, the Kathryn and Gene Bishop Distinguished Chair in Pediatric Research, the director of the Hamon Laboratory for Stem Cells and Cancer, and a Cancer Prevention and Research Institute of Texas Scholar. This work was supported by the National Institutes of Health (DK118745 and AG024945), the Josephine Hughes Sterling Foundation, and the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation (all to S.J.M.). R.J.B. was supported by a Ruth L. Kirschstein National Research Service Award Postdoctoral Fellowship from the National Heart, Lung, and Blood Institute (F32HL122095-01). We thank N. Loof, C. Cantu, T. Shih, G. Wilson, and the Moody Foundation Flow Cytometry Facility; M. Mulkey for mouse colony management; and the BioHPC high-performance computing cloud at the University of Texas South-western Medical Center for providing computational resources. This article is subject to HHMI{\textquoteright}s Open Access to Publications policy. HHMI laboratory heads have previously granted a nonexclusive CC BY 4.0 license to the public and a sublicensable license to HHMI in their research articles. Pursuant to those licenses, the author-accepted manuscript of this article can be made freely available under a CC BY4.0 license immediately upon publication. Publisher Copyright: {\textcopyright} 2022 Burgess et al.",
year = "2022",
month = aug,
day = "1",
doi = "10.1101/gad.349917.122",
language = "English (US)",
volume = "36",
pages = "887--900",
journal = "Genes and Development",
issn = "0890-9369",
publisher = "Cold Spring Harbor Laboratory Press",
number = "15-16",
}