Selenoprotein-Mediated Redox Regulation Shapes the Cell Fate of HSCs and Mature lineages [scRNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1110209 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28992104_1.fastq.gz | Fastqsanger.gz | |||
| SRR28992104_2.fastq.gz | Fastqsanger.gz | |||
| SRR28992105_1.fastq.gz | Fastqsanger.gz | |||
| SRR28992105_2.fastq.gz | Fastqsanger.gz | |||
| SRR28992106_1.fastq.gz | Fastqsanger.gz |
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Project description:The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. First, we observed a notable mRNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs). Therefore, we employed tRNAsec gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis, revealing the insights into the protective roles of selenoproteins in preserving HSC stemness and facilitating B cell maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs’ self-renewal capacity, reminiscent of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and Pre-B cells. While Trsp KO activated an antioxidant response transcription factor NRF2 across all hematopoietic cells, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in Pre-B cells of Trsp KO mice and the KO Pre-B/Pro-B cells displayed differentiation toward CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B to myeloid switch. Collectively, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and highlight the preventive potential of selenoproteins against aging-related hematopoietic alterations.
2025-03-26 | GSE267190 | GEO
Project description:The maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. First, we observed a notable mRNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs). Therefore, we employed tRNAsec gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis, revealing the insights into the protective roles of selenoproteins in preserving HSC stemness and facilitating B cell maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs’ self-renewal capacity, reminiscent of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and Pre-B cells. While Trsp KO activated an antioxidant response transcription factor NRF2 across all hematopoietic cells, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in Pre-B cells of Trsp KO mice and the KO Pre-B/Pro-B cells displayed differentiation toward CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B to myeloid switch. Collectively, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and highlight the preventive potential of selenoproteins against aging-related hematopoietic alterations.
2025-03-26 | GSE267189 | GEO
Project description:Selenoprotein-Mediated Redox Regulation Shapes the Cell Fate of HSCs and Mature lineages [bulkRNA-seq]
| PRJNA1110210 | ENA
Project description:AbstractThe maintenance of cellular redox balance is crucial for cell survival and homeostasis and is disrupted with aging. Selenoproteins, comprising essential antioxidant enzymes, raise intriguing questions about their involvement in hematopoietic aging and potential reversibility. Motivated by our observation of messenger RNA downregulation of key antioxidant selenoproteins in aged human hematopoietic stem cells (HSCs) and previous findings of increased lipid peroxidation in aged hematopoiesis, we used selenocysteine transfer RNA (tRNASec) gene (Trsp) knockout (KO) mouse model to simulate disrupted selenoprotein synthesis. This revealed insights into the protective roles of selenoproteins in preserving HSC stemness and B-lineage maturation, despite negligible effects on myeloid cells. Notably, Trsp KO exhibited B lymphocytopenia and reduced HSCs' self-renewal capacity, recapitulating certain aspects of aged phenotypes, along with the upregulation of aging-related genes in both HSCs and pre-B cells. Although Trsp KO activated an antioxidant response transcription factor NRF2, we delineated a lineage-dependent phenotype driven by lipid peroxidation, which was exacerbated with aging yet ameliorated by ferroptosis inhibitors such as vitamin E. Interestingly, the myeloid genes were ectopically expressed in pre-B cells of Trsp KO mice, and KO pro-B/pre-B cells displayed differentiation potential toward functional CD11b+ fraction in the transplant model, suggesting that disrupted selenoprotein synthesis induces the potential of B-to-myeloid switch. Given the similarities between the KO model and aged wild-type mice, including ferroptosis vulnerability, impaired HSC self-renewal and B-lineage maturation, and characteristic lineage switch, our findings underscore the critical role of selenoprotein-mediated redox regulation in maintaining balanced hematopoiesis and suggest the preventive potential of selenoproteins against aging-related alterations.
| S-EPMC11923430 | biostudies-literature
Project description:Selenium, one of a class of selenocysteine-containing proteins (selenoproteins), is an essential micronutrient known for its cancer prevention properties. Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LCMS/ MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.
2016-08-29 | GSE85943 | GEO
Project description:Thioredoxin/glutathione reductase (TGR, TXNRD3) is a selenoprotein composed of thioredoxin reductase and glutaredoxin domains; the function of this enzyme remains unknown. This NADPH-dependent thiol oxidoreductase evolved by gene duplication within the Txnrd family, is expressed in the testes and can reduce both thioredoxin and glutathione in vitro. To characterize the function of TXNRD3 in vivo, we generated a strain of mice with the deletion of Txnrd3 gene. We show that Txnrd3 knockout mice are viable and without discernable gross phenotypes, but TXNRD3 deficiency leads to fertility impairment in male mice. Txnrd3 knockout animals exhibit a lower fertilization rate in vitro, a sperm movement phenotype and an altered redox status of thiols. Proteomic analyses revealed a broad range of substrates reduced by TXNRD3 during sperm maturation, presumably as a part of quality control. The results show that TXNRD3 plays a critical role in male reproduction via the thiol redox control of spermatogenesis.
2022-10-13 | PXD033872 | Pride
Project description:Mammalian mRNAs are generated by complex and coordinated biogenesis pathways and acquire 5'-end m7G caps that play fundamental roles in processing and translation. Here we show that several selenoprotein mRNAs are not recognized efficiently by translation initiation factor eIF4E because they bear a hypermethylated cap. This cap modification is acquired via a 5’end maturation pathway similar to that of the small nucle(ol)ar RNAs (sn- and snoRNAs). Our findings also establish that the trimethylguanosine synthase 1 (Tgs1) interacts with selenoprotein mRNAs for cap hypermethylation and that assembly chaperones and core proteins devoted to sn- and snoRNP maturation contribute to recruiting Tgs1 to selenoprotein mRNPs. We further demonstrate that the hypermethylated-capped selenoprotein mRNAs localize to the cytoplasm, are associated with polysomes and thus translated. Moreover, we found that the activity of Tgs1, but not of eIF4E, is required for the synthesis of the GPx1 selenoprotein in vivo.
2014-05-14 | GSE57625 | GEO
Project description:Mammalian mRNAs are generated by complex and coordinated biogenesis pathways and acquire 5'-end m7G caps that play fundamental roles in processing and translation. Here we show that several selenoprotein mRNAs are not recognized efficiently by translation initiation factor eIF4E because they bear a hypermethylated cap. This cap modification is acquired via a 5M-bM-^@M-^Yend maturation pathway similar to that of the small nucle(ol)ar RNAs (sn- and snoRNAs). Our findings also establish that the trimethylguanosine synthase 1 (Tgs1) interacts with selenoprotein mRNAs for cap hypermethylation and that assembly chaperones and core proteins devoted to sn- and snoRNP maturation contribute to recruiting Tgs1 to selenoprotein mRNPs. We further demonstrate that the hypermethylated-capped selenoprotein mRNAs localize to the cytoplasm, are associated with polysomes and thus translated. Moreover, we found that the activity of Tgs1, but not of eIF4E, is required for the synthesis of the GPx1 selenoprotein in vivo. In total 7 samples; 3 control IP (HeLa 1,2 & 9), 2 TGS1-SF IP(C2 & C2b) and 2 TGS1-LF IP(C7 & C7b)
2014-05-14 | E-GEOD-57625 | biostudies-arrayexpress
Project description:Transcriptome analysis of bulk-HSCs, LT-HSCs and ST-HSCs.
| PRJNA941818 | ENA
Project description:Long-term hematopoietic stem cells (LT-HSCs) reside in bone marrow (BM) niches with low levels of oxygen and reactive oxygen species (ROS). ROS enhancement results in differentiation of LT-HSCs. Redox disturbances are involved in BM failure and leukemia. Paraoxonase-2 (PON2) has been shown to be important for ROS control. However, the role of PON2 in the hematopoietic system has not been addressed. Analysis of young mice with inactivated Pon2 gene (Pon2-/- mice; 3 months) revealed changes in quantity of hematopoietic stem and progenitor cells (HSPCs), which indicate changes in cell differentiation. Experiments with aged PON2-/- mice (>9 months) showed alterations of the HSPC compartment indicating changed self-renewal ability of HSCs and myeloid skewing. Reciprocal BM transplantation reveals cell intrinsic as well as extrinsic phenotypes. We observed markedly enhanced superoxide levels in BM as well as slightly enhanced total ROS level in short term (ST)-HSCs and multipotent progenitor cells (MPPs) of young mice. In aged mice, total ROS level was slightly increased in all 3 fractions of the Lin-, Sca1+, ckit+ (LSK) population. No changes in the amount of DNA double-strand breaks in LSK cells and decreased apoptosis rates in LT-HSCs of young as well as LT- and ST-HSCs of aged PON2-/- mice were seen, indicating a strong compensation mechanism. Changes of gene expression in PON2-/- LT-HSCs identified by RNA sequencing strengthened our conclusions. Additionally, competitive and serial bone marrow transplantation experiments exposed advantages of PON2-/- BMCs in multi-lineage reconstitution. Collectively, these analyses propose PON2 as crucial redox control enzyme in HSCs.
2021-07-20 | GSE122553 | GEO