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MYSM1 maintains ribosomal protein gene expression in hematopoietic stem cells to prevent hematopoietic dysfunction
Jad I. Belle, … , David Langlais, Anastasia Nijnik
Jad I. Belle, … , David Langlais, Anastasia Nijnik
Published July 9, 2020
Citation Information: JCI Insight. 2020;5(13):e125690. https://doi.org/10.1172/jci.insight.125690.
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Research Article Hematology Stem cells

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

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Abstract

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.

Authors

Jad I. Belle, HanChen Wang, Amanda Fiore, Jessica C. Petrov, Yun Hsiao Lin, Chu-Han Feng, Thi Tuyet Mai Nguyen, Jacky Tung, Philippe M. Campeau, Uta Behrends, Theresa Brunet, Gloria Sarah Leszinski, Philippe Gros, David Langlais, Anastasia Nijnik

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Figure 7

Loss of p53 rescues the anemia phenotype caused by Mysm1 deficiency.

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Loss of p53 rescues the anemia phenotype caused by Mysm1 deficiency.
The...
The data presented are from WT, p53–/–, Mysm1–/–, Mysm1–/– p53+/–, and Mysm1–/– p53–/– mice. (A) Hematology analysis of erythrocyte counts in peripheral blood of the mice. (B) MEP cell number in mouse BM, presented per 1 tibia and femur, gating on Lin–cKit+Sca1– CD34–CD16/32–CD127– cells. (C) Hematocrit and blood hemoglobin concentration. (D) MCV, MCH, and MCHC parameters. (E) Hematology analysis of leukocyte and lymphocyte counts in mouse blood. Mean ± SEM from ≥ 3 mice per genotype is presented; statistical comparisons using 1-way ANOVA with Bonferroni’s post hoc test; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

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