The splicing factor Prpf31 is required for hematopoietic stem and progenitor cell expansion during zebrafish embryogenesis
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ABSTRACT:
PROVIDER: PRJNA720429 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14168549_1.fastq.gz | Fastqsanger.gz | |||
| SRR14168549_2.fastq.gz | Fastqsanger.gz | |||
| SRR14168550_1.fastq.gz | Fastqsanger.gz | |||
| SRR14168550_2.fastq.gz | Fastqsanger.gz | |||
| SRR14168551_1.fastq.gz | Fastqsanger.gz |
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Project description:Pre-mRNA splicing is a precise regulated process, and is crucial for system development and homeostasis maintenance. Mutations in spliceosomal components have been found in various hematopoietic malignancies (HMs), and have been considered as oncogenic derivers of HMs. However, the role of spliceosomal components in normal and malignant hematopoiesis remain largely unknown. Pre-mRNA processing factor 31 (PRPF31) is a constitutive spliceosomal component, which mutations are associated with autosomal dominant retinitis pigmentosa. PRPF31 was found to be mutated in several HMs, but the function of PRPF31 in normal hematopoiesis has not been explored. In this study, we generated a prpf31 knockout zebrafish line, and discovered that prpf31 mutants exhibited severe defects in hematopoietic stem and progenitor cell (HSPC) expansion and its sequentially differentiated lineages. Immunofluorescence results showed that Prpf31 deficient HSPCs underwent malformed mitosis and M phase arrest during HSPC expansion. Transcriptome analysis and experimental validations revealed that Prpf31 deficiency extensively perturbed the alternative splicing of mitosis-related genes. Collectively, our findings elucidate a previously undescribed role for Prpf31 in HSPC expansion, through regulating the alternative splicing of mitosis-related genes.
2022-04-07 | GSE171661 | GEO
Project description:Pre-mRNA splicing is a precise regulated process and is crucial for system development and homeostasis maintenance. Mutations in spliceosomal components have been found in various hematopoietic malignancies (HMs) and have been considered as oncogenic derivers of HMs. However, the role of spliceosomal components in normal and malignant hematopoiesis remains largely unknown. Pre-mRNA processing factor 31 (PRPF31) is a constitutive spliceosomal component, which mutations are associated with autosomal dominant retinitis pigmentosa. PRPF31 was found to be mutated in several HMs, but the function of PRPF31 in normal hematopoiesis has not been explored. In our previous study, we generated a prpf31 knockout (KO) zebrafish line and reported that Prpf31 regulates the survival and differentiation of retinal progenitor cells by modulating the alternative splicing of genes involved in mitosis and DNA repair. In this study, by using the prpf31 KO zebrafish line, we discovered that prpf31 KO zebrafish exhibited severe defects in hematopoietic stem and progenitor cell (HSPC) expansion and its sequentially differentiated lineages. Immunofluorescence results showed that Prpf31-deficient HSPCs underwent malformed mitosis and M phase arrest during HSPC expansion. Transcriptome analysis and experimental validations revealed that Prpf31 deficiency extensively perturbed the alternative splicing of mitosis-related genes. Collectively, our findings elucidate a previously undescribed role for Prpf31 in HSPC expansion, through regulating the alternative splicing of mitosis-related genes.
| S-EPMC10959673 | biostudies-literature
Project description:Hematopoietic stem and progenitor cells (HSPCs) are able to self-renew and can give rise to all blood lineages throughout their lifetime, yet the mechanisms regulating HSPC development have yet to be discovered. In this study, we characterized a hematopoiesis defective zebrafish mutant line named smu07, which was obtained from our previous forward genetic screening, and found the HSPC expansion deficiency in the mutant. Positional cloning identified that slc20a1b, which encodes a sodium phosphate cotransporter, contributed to the smu07 blood phenotype. Further analysis demonstrated that mutation of slc20a1b affects HSPC expansion through cell cycle arrest at G2/M phases in a cell-autonomous manner. Our study shows that slc20a1b is a vital regulator for HSPC proliferation in zebrafish early hematopoiesis and provides valuable insights into HSPC development.
2021-01-26 | GSE165415 | GEO
Project description:Dysfunction of splicing factors often result in abnormal cell differentiation and apoptosis, especially in neural tissues. Mutations in pre-mRNAs processing factor 31 (PRPF31) cause autosomal dominant retinitis pigmentosa, a progressive retinal degeneration disease. The transcriptome-wide splicing events specifically regulated by PRPF31 and their biological roles in the development and maintenance of retina are still unclear. Here, we showed that the differentiation and viability of retinal progenitor cells (RPCs) are severely perturbed in prpf31 knockout zebrafish when compared with other tissues at an early embryonic stage. At the cellular level, significant mitotic arrest and DNA damage were observed. These defects could be rescued by the wild-type human PRPF31 rather than the disease-associated mutants. Further bioinformatic analysis and experimental verification uncovered that Prpf31 deletion predominantly causes the skipping of exons with a weak 5′ splicing site. Moreover, genes necessary for DNA repair and mitotic progression are most enriched among the differentially spliced events, which may explain the cellular and tissular defects in prpf31 mutant retinas. This is the first time that Prpf31 is demonstrated to be essential for the survival and differentiation of RPCs during retinal neurogenesis by specifically modulating the alternative splicing of genes involved in DNA repair and mitosis.
2021-01-06 | GSE151273 | GEO
Project description:The RNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of vertebrate embryogenesis and malignancies. However, its functions and underlying molecular mechanisms in the expansion of hematopoietic stem and progenitor cells (HSPCs) during early embryonic development remain elusive. Here we show that Mettl16, an RNA methyltransferase identified recently, is specifically required for HSPC expansion during zebrafish early embryonic development in an m6A-dependent manner. In mettl16 deficient embryos, HSPCs exhibit defective proliferation capacity due to G0/G1 arrest. Mechanistically, HSPC proliferation is blocked by impaired methyltransferase function of Mettl16 in vivo. We identify cell cycle gene mybl2b as a novel direct m6A target of Mettl16, and Mettl16 deficiency destabilizes mybl2b mRNA, which is mediated by m6A reader Igf2bp1. Moreover, we revealed that the METTL16-m6A-MYBL2-IGF2BP1 signaling axis in G1/S progression is conserved in humans. Collectively, our findings demonstrate the critical function of m6A modification deposited by Mettl16 in HSPC expansion during early embryonic development.
2024-03-04 | GSE225089 | GEO
Project description:The RNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of vertebrate embryogenesis and malignancies. However, its functions and underlying molecular mechanisms in the expansion of hematopoietic stem and progenitor cells (HSPCs) during early embryonic development remain elusive. Here we show that Mettl16, an RNA methyltransferase identified recently, is specifically required for HSPC expansion during zebrafish early embryonic development in an m6A-dependent manner. In mettl16 deficient embryos, HSPCs exhibit defective proliferation capacity due to G0/G1 arrest. Mechanistically, HSPC proliferation is blocked by impaired methyltransferase function of Mettl16 in vivo. We identify cell cycle gene mybl2b as a novel direct m6A target of Mettl16, and Mettl16 deficiency destabilizes mybl2b mRNA, which is mediated by m6A reader Igf2bp1. Moreover, we revealed that the METTL16-m6A-MYBL2-IGF2BP1 signaling axis in G1/S progression is conserved in humans. Collectively, our findings demonstrate the critical function of m6A modification deposited by Mettl16 in HSPC expansion during early embryonic development.
2024-03-04 | GSE225136 | GEO
Project description:Slc20a1b is essential for hematopoietic stem/progenitor cell expansion in zebrafish
| PRJNA694557 | ENA
Project description:Transcriptional profiling performed from total eye RNA extracts of wildtype control fishes versus Prpf31 morpholino injected larvae (at ~72hpf) two-condition experiment: wildtype zebrafish versus MO-Prpf31 injected zebrafish eye RNA; 6 replicates each (extraction from 6 pools (~200 eyes each) of controls and 6 pools MO-Prpf31 (~200 eyes each))
2010-05-06 | E-GEOD-20424 | biostudies-arrayexpress
Project description:During vertebrate embryogenesis, fetal hematopoietic stem and progenitor cells (HSPCs) exhibit expansion and differentiation properties in a supportive hematopoietic niche. To profile the developmental landscape of fetal HSPCs and their local niche, here, using single-cell RNA-sequencing, we deciphered a dynamic atlas covering 28,777 cells and 9 major cell types (23 clusters) of zebrafish caudal hematopoietic tissue (CHT). We characterized four heterogeneous HSPCs with distinct lineage priming and metabolic gene signatures. Furthermore, we investigated the regulatory mechanism of CHT niche components for HSPC development, with a focus on the transcription factors and ligand-receptor networks involved in HSPC expansion. Importantly, we identified an endothelial cell-specific G protein-coupled receptor 182, followed by in vivo and in vitro functional validation of its evolutionally conserved role in supporting HSPC expansion in zebrafish and mice. Finally, comparison between zebrafish CHT and human fetal liver highlighted the conservation and divergence across evolution. These findings enhance our understanding of the regulatory mechanism underlying hematopoietic niche for HSPC expansion in vivo and provide insights into improving protocols for HSPC expansion in vitro.
| S-EPMC8040670 | biostudies-literature
Project description:Hematopoietic stem cells (HSCs) are a specialized subset of cells with self-renewal and multilineage differentiation potency, which are essential for their function in bone marrow or umbilical cord blood transplantation to treat blood disorders. Expanding the hematopoietic stem and progenitor cells (HSPCs) ex vivo is essential to understand the HSPCs-based therapies potency. Here, we established a screening system in zebrafish by adopting an FDA-approved drug library to identify candidates that could facilitate HSPC expansion. To date, we have screened 171 drugs of 7 categories, including antibacterial, antineoplastic, glucocorticoid, NSAIDS, vitamins, antidepressant, and antipsychotic drugs. We found 21 drugs that contributed to HSPCs expansion, 32 drugs' administration caused HSPCs diminishment and 118 drugs' treatment elicited no effect on HSPCs amplification. Among these drugs, we further investigated the vitamin drugs ergocalciferol and panthenol, taking advantage of their acceptability, limited side-effects, and easy delivery. These two drugs, in particular, efficiently expanded the HSPCs pool in a dose-dependent manner. Their application even mitigated the compromised hematopoiesis in an ikzf1-/- mutant. Taken together, our study implied that the larval zebrafish is a suitable model for drug repurposing of effective molecules (especially those already approved for clinical use) that can facilitate HSPCs expansion.
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