Epigenetic regulation of gene expression in mouse Hematopoietic cell after Plasmodium stimulated
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE198603 | GEO | 2022/11/11
REPOSITORIES: GEO
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Project description:Plasmodium infection induced change in the Bone marrow and Blood cells. Here we addressed whether a prior Plasmodium infection would imapct the cell type and gene expression of Bone marrow and Blood cells by single cell RNA-seq.
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Project description:Severe infections are a major stress on haematopoiesis, where the consequences for haematopoietic stem cells (HSCs) have only recently started to emerge. HSC function critically depends on the integrity of complex bone marrow (BM) niches, however whether the BM microenvironment plays a role in mediating the effects of infection on HSCs remains an open question. Here, using a murine model of malaria and combining single cell RNA sequencing, mathematical modelling, transplantation assays and intravital microscopy, we show that haematopoiesis is reprogrammed upon infection, whereby the HSC compartment turns over significantly faster than in steady-state and HSC function is drastically affected as a result. Interferon is found to affect both haematopoietic and mesenchymal BM cells and we specifically identify a dramatic loss of osteoblasts and alterations in endothelial cell function. Osteo-active parathyroid hormone treatment abolishes infection-triggered HSC proliferation and, coupled with Reactive Oxygen Species quenching, enables partial rescuing of HSC function.
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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
Project description:Hematopoietic stem cells (HSC) rely on a unique regulatory machinery that facilitates life-long blood production and enables reconstitution of the entire hematopoietic system upon transplantation. However, the biological processes governing human HSC self-renewal and engraftment ability are poorly understood and challenging to recapitulate ex vivo to facilitate robust human HSC expansion. We discovered a novel HSC regulatory protein, MYCT1 (MYCT target 1), that is selectively expressed in endothelial cells (EC) and undifferentiated human HSPCs but becomes drastically downregulated during HSC culture. Lentiviral knockdown of MYCT1 in human foetal liver and cord blood HSPCs revealed a critical role for MYCT1 in governing human HSPC expansion and engraftment ability. Single cell RNAseq of human CB HSPCs after MYCT1 knockdown and overexpression revealed that MYCT1 governs HSC functional competence and modulates cellular properties essential for HSC stemness, such as low mitochondrial metabolic activity. Indeed, restoring the compromised MYCT1 expression in cultured human CB HSPCs improved ex vivo expansion of the most undifferentiated human HSPCs and enhanced their engraftment ability. We found that MYCT1 is localized in the endosomal membrane and interacts with vesicle trafficking regulators and signalling machinery essential for HSC and EC function. Loss of MYCT1 led to excessive endocytosis and hyperactive signalling responses to cytokines, whereas restoring MYCT1 expression in cultured CB HSPCs balanced the abnormal endocytosis associated with prolonged culture and fine-tuned signalling responses. Our work identifies MYCT1-moderated endocytosis and environmental sensing as an essential regulatory mechanism required to preserve human HSC stemness, and pinpoints silencing of MYCT1 as a critical contributor to the dysfunction of cultured human HSCs that needs to be addressed to improve human HSC culture strategies.
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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.
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Project description:Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.
2021-02-08 | MSV000086816 | MassIVE
Project description:The hematopoietic stem cell (HSC) compartment is heterogeneous, yet our understanding of the identities of different HSC subtypes is limited. Here we show that platelet integrin CD41 (M-NM-1IIb), currently thought to only transiently mark fetal HSCs, is expressed on an adult HSC subtype that accumulates with age. CD41+ HSCs were largely quiescent and exhibited myeloerythroid and megakaryocyte gene priming, governed by Gata1, whereas CD41- HSCs were more proliferative and exhibited lymphoid gene priming. When isolated without the use of blocking antibodies, CD41+ HSCs possessed long-term repopulation capacity upon serial transplantations and showed a marked myeloid-bias compared to CD41-HSCs, which yielded a more lymphoid-biased progeny. CD41-knockout mice displayed multilineage hematopoietic defects coupled with decreased quiescence and survival of HSCs, suggesting that CD41 is functionally relevant for HSC maintenance and hematopoietic homeostasis. Transplantation experiments indicated that CD41-KO associated defects are long-term transplantable and HSC-derived, and in part mediated through the loss of platelet mass leading to decreases in HSC exposure to important platelet released cytokines, such as TGFM-NM-21. In summary, our data provide a novel marker to identify a myeloid-biased HSC subtype that becomes prevalent with age, and highlights the dogma of HSC regulation by their progeny. For microarray analysis, 1000 HSCs were FACS sorted from pools of 4-5 mice directly into lysis buffer, RNA extracted and whole transcript amplification was performed as previously described (Gonzalez-Roca E, Garcia-Albeniz X, Rodriguez-Mulero S, Gomis RR, Kornacker K, Auer H. Accurate expression profiling of very small cell populations. PLoS One. 2010;5:e14418.)
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