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Belle, J.I.* ; Wang, H.* ; Fiore, A.* ; Petrov, J.C.* ; Lin, Y.H.* ; Feng, C.H.* ; Nguyen, T.T.M.* ; Tung, J.* ; Campeau, P.M.* ; Behrends, U.* ; Brunet, T.* ; Leszinski, G.S. ; Gros, P.* ; Langlais, D.* ; Nijnik, A.*

MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction.

JCI insight 5:e125690 (2020)
Publ. Version/Full Text DOI PMC
Open Access Gold
Ribosomopathies are congenital disorders caused by mutations in the genes encoding ribosomal and other functionally related proteins. They are characterized by anemia, other hematopoietic and developmental abnormalities, and p53 activation. Ribosome assembly requires coordinated expression of many ribosomal protein (RP) genes; however, the regulation of RP gene expression, especially in hematopoietic stem cells (HSCs), remains poorly understood. MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that HSC dysfunction in Mysm1 deficiency is driven by p53; however, the mechanisms of p53 activation remained unclear. Here, we describe the transcriptome of Mysm1-deficient mouse HSCs and identify MYSM1 genome-wide DNA binding sites. We establish a direct role for MYSM1 in RP gene expression and show a reduction in protein synthesis in Mysm1(-/-) HSCs. Loss of p53 in mice fully rescues Mysm1(-/-) anemia phenotype but not RP gene expression, indicating that RP gene dysregulation is a direct outcome of Mysm1 deficiency and an upstream mediator of Mysm1-/phenotypes through p53 activation. We characterize a patient with a homozygous nonsense MYSM1 gene variant, and we demonstrate reduced protein synthesis and increased p53 levels in patient hematopoietic cells. Our work provides insights into the specialized mechanisms regulating RP gene expression in HSCs and establishes a common etiology of MYSM1 deficiency and ribosomopathy syndromes.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Hematology ; Hematopoietic Stem Cells ; Stem Cells; Histone H2a Deubiquitinase; Dna-damage; Epigenetic Control; Self-renewal; Mouse Model; Genome; P53; Maintenance; Biogenesis; Polycomb
Language english
Publication Year 2020
HGF-reported in Year 2020
ISSN (print) / ISBN 2379-3708
e-ISSN 2379-3708
Journal JCI insight
Quellenangaben Volume: 5, Issue: 13, Pages: , Article Number: e125690 Supplement: ,
Publisher Clarivate
Publishing Place Ann Arbor, Michigan
Reviewing status Peer reviewed
Institute(s) Institute of Human Genetics (IHG)
Institute of Neurogenomics (ING)
POF-Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-500700-001
G-503292-001
Grants Cole Foundation Studentship
Canadian Foundation for Innovation (CFI)
Frederick Banting Tri-Council Scholarship
FRQS Masters Training Studentship
Max & Jane Childress Entrance Fellowship from the Department of Physiology of McGill University
Frederick Banting Tri-Council Graduate Scholarship
CIHR Neuroinflammation Training Program
FRQS
CIHR
Helmholtz Center Munich (HMGU)
German Center for Infection Research (DZIF)
Lost Voices Foundation
Weidenhammer-Zoebele Foundation
Fonds de Recherche du Quebec Sante (FRQS)
Faculty of Medicine of McGill University
Canadian Institutes of Health Research (CIHR)
DOI 10.1172/jci.insight.125690
WOS ID WOS:000568794400001
Scopus ID 85087670388
PubMed ID 32641579
Erfassungsdatum 2020-09-18
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