Ancient synteny links metabolism with erythroid development
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ABSTRACT:
PROVIDER: PRJNA1141519 | ENA |
REPOSITORIES: ENA
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Project description:Generation of mature cells from progenitors requires tight coupling of differentiation and metabolism. During erythropoiesis, erythroblasts are required to massively upregulate globin synthesis then clear extraneous material and enucleate to produce erythrocytes1-3. Nprl3 has remained in synteny with the α-globin genes for >500 million years4, and harbours the majority of the α-globin enhancers5. Nprl3 is a highly conserved inhibitor of mTORC1, which controls cellular metabolism. However, whether Nprl3 itself serves an erythroid role is unknown. Here, we show that Nprl3 is a key regulator of erythroid metabolism. Using Nprl3-deficient fetal liver and adult competitive bone marrow - fetal liver chimeras, we show that NprI3 is required for sufficient erythropoiesis. Loss of Nprl3 elevates mTORC1 signalling, suppresses autophagy and disrupts erythroblast glycolysis and redox control. Human CD34+ progenitors lacking NPRL3 produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Finally, we show that the α-globin enhancers upregulate NprI3 expression, and that this activity is necessary for optimal erythropoiesis. Therefore, the anciently conserved linkage of NprI3, α-globin and their associated enhancers has enabled coupling of metabolic and developmental control in erythroid cells. This may enable erythropoiesis to adapt to fluctuating nutritional and environmental conditions.
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Project description:Development of red blood cells from progenitors requires profound reshaping of both gene expression and metabolism. How these processes are coupled is unclear. Nprl3, an inhibitor of mTORC1, has remained in synteny with the -globin genes for >500 million years, and harbours most of the -globin enhancers. However, whether Nprl3 itself serves an erythroid role is unknown. While hematopoietic progenitors rely on tonic expression of baseline Nprl3, erythroblasts experience ‘boosted’ Nprl3 expression. Using Nprl3-deficient fetal liver and adult competitive bone marrow - fetal liver chimaeras, we show that NprI3 is required for sufficient erythropoiesis. Loss of Nprl3 elevates mTORC1 signalling, suppresses autophagy and disrupts erythroblast glycolysis. Human NPRL3-knockout erythroid progenitors produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Thus, Nprl3 is a key regulator of erythroid metabolism. Finally, we show that the alpha-globin enhancers upregulate erythoid NprI3 expression, and that this activity supports optimal erythropoiesis.
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Project description:To explore the mechanisms controlling erythroid differentiation and development in human, we analyzed the genome-wide transcription dynamics that occurs during the differentiation of HESCs into the erythroid lineage and development of embryonic to adult erythropoiesis using high throughput sequencing technology. Undifferentiated HESCs as well as erythroid cells at three developmental stages-ESER (embryonic stage), FLER (fetal stage) and PBER (adult stage)-were analyzed. Our findings revealed that the number of expressed genes decreased during the differentiation, while the total expression intensity increased. At the 3 transitions (HESC-ESER, ESER-FLER and FLER-PBER), differential expression of many types of genes was observed at every transition. These differentially expressed genes were involved in maintaining the pluripotency of stem cells, early erythroid specification, rapid cell growth and enucleation potential. In addition, differentially expressed genes were found to constitute networks and central nodes at each transition. Clusters of genes in some chromosomal regions switched between expression and silence. We also discovered that differentially expressed genes constituted networks and central nodes of them in each transition. Our studies provide a fundamental basis for further investigation of erythroid differentiation and development. Compare the transcriptome of embryonic stem cells and three erythroid cell types at different developmental stages
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Project description:Metabolic programs contribute to hematopoietic stem and progenitor cell (HSPC) fate, but it is not known whether the metabolic regulation of protein synthesis controls HSPC differentiation. Here, we show that SLC7A1/CAT1-dependent arginine uptake and its catabolism to the polyamine spermidine control human erythroid specification of HSPCs via activation of the eukaryotic translation initiation factor 5A (eIF5A). eIF5A activity is dependent on its hypusination, a post-translational modification resulting from the conjugation of the aminobutyl moiety of spermidine to lysine. Notably, attenuation of hypusine synthesis in erythroid progenitors by inhibition of deoxyhypusine synthase abrogates erythropoiesis but not myeloid cell differentiation. Proteomic profiling reveals mitochondrial translation to be a critical target of hypusinated eIF5A and accordingly, progenitors with decreased hypusine activity exhibit diminished oxidative phosphorylation. This impacted pathway is critical for eIF5A-regulated erythropoiesis as interventions augmenting mitochondrial function partially rescue human erythropoiesis under conditions of attenuated hypusination. Levels of mitochondrial ribosomal proteins were especially sensitive to the loss of hypusine and we find that the ineffective erythropoiesis linked to haploinsufficiency of RPS14 in del(5q) myelodysplastic syndrome is associated with a diminished pool of hypusinated eIF5A. Moreover, patients with RPL11-haploinsufficient Diamond-Blackfan anemia as well as CD34+ progenitors with downregulated RPL11 exhibit a markedly decreased hypusination in erythroid progenitors, concomitant with a loss of mitochondrial metabolism. Thus, eIF5A-dependent protein synthesis regulates human erythropoiesis and our data reveal a novel role for RPs in controlling eIF5A hypusination in HSPC, synchronizing mitochondrial metabolism with erythroid differentiation.
2023-01-25 | MSV000091139 | MassIVE
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to compare NGS-derived transcriptome profiling (RNA-seq) and transposon insertion mutagenesis (Tnseq) libraries of Lon deletions compared to wt Caulobacter crescentus. Methods: See Methods section of The Lon protease links nucleotide metabolism with proteotoxic stress for information regarding methods or contact lead correspondence. Briefly, Samples for RNAseq were extracted from wt and lon deletion strains grown to mid exponential phase. Methods: See Methods section of The Lon protease links nucleotide metabolism with proteotoxic stress for information regarding methods or contact lead correspondence. Briefly, Samples for Tnseq were generated by Eztn5 transposon mutagenesis. Conclusions: Our study represents the first detailed analysis of lon deletion comparison to wt caulobacter transcriptomes, with biologic replicates, generated by RNA-seq technology.
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