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

ABSTRACT: MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that HSC dysfunction in Mysm1-deficiency is driven by p53 stress response, however, the molecular function of MYSM1 as a transcriptional activator and its essential role in p53 stress response repression remain difficult to reconcile. Here, we performed genome-wide analyses of MYSM1-regulated genes in hematopoietic stem and progenitor cells (HSPCs). This included RNA-Seq of sorted Mysm1-deficient mouse HSCs and MPPs, and ChIP-Seq mapping of MYSM1 DNA-binding sites in hematopoietic progenitor cell lines. We demonstrate a direct role for MYSM1 in the regulation of genes encoding protein components of the ribosome (RP-genes) and other regulators of translation. Mechanistically, the dysregulation of RP-genes in Mysm1-deficiency was upstream of p53-activation and associated with reduced HSCs protein synthesis rates and p53-dependent anemia.

ORGANISM(S): Mus musculus

PROVIDER: GSE150666 | GEO | 2020/07/28

REPOSITORIES: GEO

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

Project description:MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that HSC dysfunction in Mysm1-deficiency is driven by p53 stress response, however, the molecular function of MYSM1 as a transcriptional activator and its essential role in p53 stress response repression remain difficult to reconcile. Here, we performed genome-wide analyses of MYSM1-regulated genes in hematopoietic stem and progenitor cells (HSPCs). This included RNA-Seq of sorted Mysm1-deficient mouse HSCs and MPPs, and ChIP-Seq mapping of MYSM1 DNA-binding sites in hematopoietic progenitor cell lines. We demonstrate a direct role for MYSM1 in the regulation of genes encoding protein components of the ribosome (RP-genes) and other regulators of translation. Mechanistically, the dysregulation of RP-genes in Mysm1-deficiency was upstream of p53-activation and associated with reduced HSCs protein synthesis rates and p53-dependent anemia.

2020-07-28 | GSE150663 | GEO

Repression of p53-target gene Bbc3/puma by MYSM1 is essential for the survival of hematopoietic multipotent progenitors and contributes to stem cell maintenance

Project description:MYSM1 is a transcriptional regulator essential for HSC function and hematopoiesis. We established that p53 activation is a common mechanism mediating HSC dysfunction, MPP depletion, and lymphopenia in Mysm1-deficiency, however, the specific p53-induced effectors that trigger dysfunction in Mysm1-deficient HSPCs remain unknown. Here, we performed RNA-Seq of Lin-cKit+Sca1+CD150+ and CD150- HSPCs from Mysm1-/-Puma-/-, Mysm1-/-Puma+/-, Puma-/-, and wild-type mice; (Mysm1-/-Puma+/- phenocopies Mysm1-/-). We showed that Bbc3/PUMA is the primary non-redundant mediator of MPP depletion in Mysm1-deficiency and contributes to HSC dysfunction, whereas depletion of lymphoid-lineage cells involves PUMA-independent p53 activities. We also identified a broad downregulation of genes encoding protein components of the ribosome (RP-genes) and other regulators of translation in Mysm1-deficiency, and the downregulation persisted in Mysm1-/-Puma-/-.

2020-07-22 | GSE150665 | GEO

Mitochondrial respiratory chain is essential for hematopoietic stem cell function

Project description:Adult and fetal hematopoietic stem cells (HSCs) display a glycolytic phenotype, which is required for maintenance of stemness; however, whether mitochondrial respiration is required to maintain HSC function is not known. Here we report that loss of the mitochondrial complex III subunit Rieske iron sulfur protein (RISP) in fetal mouse HSCs allows them to proliferate but impairs their differentiation, resulting in anemia and prenatal death. RISP null fetal HSCs displayed impaired respiration resulting in a decreased NAD+/NADH ratio. RISP null fetal HSCs and progenitors exhibited an increase in both DNA and histone methylation concomitant with increases in 2-hydroxyglutarate (2-HG), a metabolite known to inhibit DNA and histone demethylases. RISP inactivation in adult HSCs also impaired respiration resulting in loss of quiescence resulting in severe pancytopenia and lethality. Thus, respiration is dispensable for adult or fetal HSC proliferation, but essential for fetal HSC differentiation and maintenance of adult HSC quiescence.

2017-09-13 | PXD006054 | Pride

p53-Dependent Induction of P2X7 on Hematopoietic Stem and Progenitor Cells Regulates Hematopoietic Response to Genotoxic Stress [RNA-seq]

Project description:Stem and progenitor cells are the main mediators of tissue renewal and repair, both under homeostatic conditions and in the response to physiological stress and injury. Hematopoietic system is responsible for the regeneration of blood and immune cells, and is maintained by bone marrow resident hematopoietic stem and progenitor cells (HSPCs). Hematopoietic system is particularly susceptible to injury in response to genotoxic stress, resulting in risk of bone marrow failure and secondary malignancies in cancer patients undergoing radiotherapy. Here we analyze the in vivo transcriptional response of HSPCs to genotoxic stress in a mouse whole body irradiation model, and together with p53 ChIP-Seq and studies in p53-knockout (p53KO) mice, characterize the p53-dependent and p53-independent branches of this transcriptional response. Our work demonstrates the p53-independent induction of inflammatory transcriptional signatures in HSPCs in response to genotoxic stress, and identifies multiple novel p53-target genes induced in HSPCs in response to whole body irradiation. In particular, we establish the direct p53-mediated induction of P2X7 expression on HSCs and HSPCs in response to genotoxic stress. We further demonstrate the role of P2X7 in hematopoietic response to acute genotoxic stress, with P2X7-deficiency significantly extending mouse survival in irradiation-induced hematopoietic failure. We also demonstrate the role of P2X7 in the context of long-term HSC regenerative fitness following sublethal irradiation. Overall our studies provide important insights into the mechanisms of HSC response to genotoxic stress and further suggests P2X7 as a target for pharmacological modulation of HSC fitness and hematopoietic response to genotoxic injury.

2021-10-09 | GSE171691 | GEO

p53-Dependent Induction of P2X7 on Hematopoietic Stem and Progenitor Cells Regulates Hematopoietic Response to Genotoxic Stress [ChIP-seq]

2021-10-09 | GSE171694 | GEO

Probing secretome of hematopoietic and mesenchymal stem cell interactions in single and co-cultures

Project description:Hematopoietic stem cells (HSCs) primarily reside in the bone marrow, where they receive external cues from their local microenvironment. The complex milieu of biophysical cues, cellular components, and cell-secreted factors regulates the process by which HSC produce the blood and immune system. We previously showed direct co-culture of primary murine hematopoietic stem and progenitor cells with a population of marrow-derived mesenchymal stromal and progenitor cells (MSPCs) in a methacrylamide-functionalized gelatin (GelMA) hydrogel improves hematopoietic progenitor maintenance. However, the mechanism by which MSPCs influenced HSC fate decisions remained unknown. Herein, we report the use of proteomic analysis to correlate HSC phenotype to a broad candidate pool of 200 soluble factors produced by combined mesenchymal and hematopoietic progeny. Partial Least Squares Regression (PLSR), along with an iterative filter method, identified TGFβ-1, MMP-3, c-RP, and TROY as positively correlated with HSC maintenance. Experimentally, we then observe exogenous stimulation of HSC monocultures in GelMA hydrogels with these combined cytokines increases the ratio of hematopoietic progenitors to committed progeny after a 7-day culture 7.52 ± 3.65 fold compared to non-stimulated monocultures. Findings suggest a cocktail of the downselected cytokines amplify hematopoietic maintenance potential of HSCs beyond that of MSPC-secreted factors alone. This work integrates empirical and computation methods to identify cytokine combinations to improve HSC maintenance within an engineered HSC niche, suggesting a route towards identifying feeder-free culture platforms for HSC expansion.

2020-01-22 | GSE143987 | GEO

PRMT5 Modulates Splicing in Hematopoietic Stem Cells

Project description:This study aimed to clarify the role of PRMT5 in the hematopoietic stem cell (HSC) compartment, and elucidate the functional relevance of PRMT5-mediated splicing in HSCs. We confirm the cell intrinsic requirement for PRMT5 in HSC maintenance, and present evidence suggesting that PRMT5 deficiency perturbs HSC proteostasis. Notably, we also uncover a critical role for PRMT5 in maintaining HSC genomic integrity by modulating splicing of genes involved in DNA repair; loss of which leads to unresolved DNA damage, p53 activation and rapid HSC exhaustion. Overall, these findings establish PRMT5-mediated splicing as a major determinant of HSC fate, and highlight the need to maintain an adequate level of PRMT5 activity in HSCs.

2019-03-03 | GSE116674 | GEO

MYSM1

Project description:MYSM1

| PRJNA633122 | ENA

Molecular characterization of hematopoietic stem cells after in vitro amplification on biomimetic 3D PDMS cell culture scaffoldsMolecular characterization of hematopoietic stem cells after in vitro amplification on biomimetic 3D PDMS cell culture scaffolds

Project description:Hematopoietic stem cell transplantation (HSCT) is successfully applied since the late 1950s, however, its efficacy still needs to be improved. A promising strategy is to transplant high numbers of pluripotent hematopoietic stem cells (HSCs). Therefore, an advanced ex vivo culture system is needed that supports the proliferation and maintains the pluripotency of HSC to override possible limitations in cell numbers gained from donors. To model the natural HSC niche in vitro and thus, to amplify high numbers of undifferentiated HSCs, we used an optimized HSC cell culture medium in combination with artificial 3D bone marrow-like scaffolds made of polydimethylsiloxane (PDMS). After 14 days in vitro (DIV) cell culture, we performed transcriptome and proteome analysis of the whole cell populations. Ingenuity pathway analysis (IPA) indicated that our 3D PDMS cell culture scaffolds activated interleukin, SREBP, mTOR and FOXO signaling pathways as well as the HSC metabolism, which we confirmed by ELISA, Western blot and metabolic flux analysis. These molecular signaling pathways and HSC metabolism are well known to promote the expansion HSCs and are involved in their pluripotency maintenance. After selection and enrichment of immature CD34-positive/CD38-negative HSCs using FACS sorting, we could confirm our findings by another proteome analysis followed by IPA. Thus, we could show that our 3D bone marrow-like PDMS scaffolds activate key molecular signaling pathways to amplify the numbers of undifferentiated HSC efficiently ex vivo.

2021-11-10 | PXD025849 | Pride

Aspp1 Preserves Hematopoietic Stem Cell Pool Integrity and Prevents Malignant Transformation

Project description:Quiescent hematopoietic stem cells (HSCs) are prone to mutagenesis, and accumulation of mutations can result in hematological malignancies. The mechanisms through which HSCs prevent such detrimental accumulation, however, are unclear. Here, we show that Aspp1 coordinates with p53 to maintain the genomic integrity of the HSC pool. Aspp1 is preferentially expressed in HSCs and restricts HSC pool size by attenuating self-renewal under steady state conditions. After genotoxic stress, Aspp1 promotes HSC cycling and induces p53-dependent apoptosis in cells with persistent DNA damage foci. Beyond these p53-dependent functions, Aspp1 attenuates HSC self-renewal and accumulation of DNA damage in p53-null HSCs. Consequently, concomitant loss of Aspp1 and p53 leads to the development of hematological malignancies, especially T-cell leukemia and lymphoma. Together, these data highlights coordination between Aspp1 and p53 in regulating HSC self-renewal and DNA damage tolerance, and suggest that HSCs possess specific mechanisms that prevent accumulation of mutations and malignant transformation. 8-week-old WT, Aspp1-/-, Mx1-Cre(+)p53flox/flox and Mx1-Cre(+)Aspp1-/-p53flox/flox mice were intraperitoneally administered with 400 μg pIpC five times every other day to obtain WT, Aspp1-/-, p53-/- and Aspp1-/-p53-/- bone marrow. 4 weeks after pIpC treatment, bone marrow lineage(-) Sca-1(+) cKit(+) cells were isolated. RNA was extracted and pooled from 3 independent mice per genotype. RNA samples were then amplified, labeled, and hybridized to independent arrays.

2015-05-20 | E-GEOD-69032 | biostudies-arrayexpress

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