SF3B1 deficiency impairs human erythropoiesis via activation of p53 pathway: implications for understanding of ineffective erythropoiesis in MDS
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA724732 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14312070_1.fastq.gz | Fastqsanger.gz | |||
| SRR14312070_2.fastq.gz | Fastqsanger.gz | |||
| SRR14312071_1.fastq.gz | Fastqsanger.gz | |||
| SRR14312071_2.fastq.gz | Fastqsanger.gz | |||
| SRR14312072_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
Project description:SF3B1 knockdown in human CD34+ cells leads to increased apoptosis and cell cycle arrest of early-stage erythroid cells and generation of abnormally nucleated late-stage erythroblasts. RNA-seq analysis of SF3B1-knockdown erythroid progenitor CFU-E cells revealed altered splicing of an E3 ligase Makorin Ring Finger Protein 1 (MKRN1) and subsequent activation of p53 pathway.Decreased expression of genes involved in mitosis/cytokinesis pathway including polo-like kinase 1 (PLK1) was noted in SF3B1-knockdown polychromatic and orthochromatic erythroblasts comparing to control cells.
2021-04-24 | GSE173232 | GEO
Project description:BACKGROUND:SF3B1 is a core component of splicing machinery. Mutations in SF3B1 are frequently found in myelodysplastic syndromes (MDS), particularly in patients with refractory anemia with ringed sideroblasts (RARS), characterized by isolated anemia. SF3B1 mutations have been implicated in the pathophysiology of RARS; however, the physiological function of SF3B1 in erythropoiesis remains unknown. METHODS:shRNA-mediated approach was used to knockdown SF3B1 in human CD34+ cells. The effects of SF3B1 knockdown on human erythroid cell differentiation, cell cycle, and apoptosis were assessed by flow cytometry. RNA-seq, qRT-PCR, and western blot analyses were used to define the mechanisms of phenotypes following knockdown of SF3B1. RESULTS:We document that SF3B1 knockdown in human CD34+ cells leads to increased apoptosis and cell cycle arrest of early-stage erythroid cells and generation of abnormally nucleated late-stage erythroblasts. RNA-seq analysis of SF3B1-knockdown erythroid progenitor CFU-E cells revealed altered splicing of an E3 ligase Makorin Ring Finger Protein 1 (MKRN1) and subsequent activation of p53 pathway. Importantly, ectopic expression of MKRN1 rescued SF3B1-knockdown-induced alterations. Decreased expression of genes involved in mitosis/cytokinesis pathway including polo-like kinase 1 (PLK1) was noted in SF3B1-knockdown polychromatic and orthochromatic erythroblasts comparing to control cells. Pharmacologic inhibition of PLK1 also led to generation of abnormally nucleated erythroblasts. CONCLUSIONS:These findings enabled us to identify novel roles for SF3B1 in human erythropoiesis and provided new insights into its role in regulating normal erythropoiesis. Furthermore, these findings have implications for improved understanding of ineffective erythropoiesis in MDS patients with SF3B1 mutations.
| S-EPMC5810112 | biostudies-literature
Project description:Myelodysplastic syndromes (MDS) with mutated SF3B1 gene have many features including a favorable outcome that are distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we show that SF3B1-mutated MDS are characterized by a dramatically reduced R-loop formation predominating in gene bodies, which tightly associates with reduced retention of introns specifically found in SF3B1-mutated, but not in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibited augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation, which were recapitulated in murine Sf3b1K700E/+ proerythroblasts. Importantly, R-loop formation was restored by histone deacetylase inhibition using SAHA/vorinostat, which improved Sf3b1K700E/+ erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress is a hallmark of SF3B1- mutated MDS ineffective erythropoiesis, which could be used as a new therapeutic target.
2024-05-29 | PXD038656 | Pride
Project description:Myelodysplastic syndromes (MDS) with mutated SF3B1 gene have many features including a favorable outcome that are distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we show that SF3B1-mutated MDS are characterized by a dramatically reduced R-loop formation predominating in gene bodies, which tightly associates with reduced retention of introns specifically found in SF3B1-mutated, but not in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibited augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation, which were recapitulated in murine Sf3b1K700E/+ proerythroblasts. Importantly, R-loop formation was restored by histone deacetylase inhibition using SAHA/vorinostat, which improved Sf3b1K700E/+ erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress is a hallmark of SF3B1- mutated MDS ineffective erythropoiesis, which could be used as a new therapeutic target.
2024-04-08 | PXD038700 | Pride
Project description:Normal and ineffective erythropoiesis scRNA seq
| PRJNA920516 | ENA
Project description:Myelodysplastic syndromes (MDS) with mutated SF3B1 gene have many features including a favorable outcome that are distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we show that SF3B1-mutated MDS are characterized by a dramatically reduced R-loop formation predominating in gene bodies, which associates with intron retention reduction specifically found in SF3B1-mutated, but not in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibited augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restored Rloop formation,slowed down DNA replication forks and improved SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress is a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a new therapeutic target.
2024-02-22 | GSE220525 | GEO
Project description:Myelodysplastic syndromes (MDS) with mutated SF3B1 gene have many features including a favorable outcome that are distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we show that SF3B1-mutated MDS are characterized by a dramatically reduced R-loop formation predominating in gene bodies, which associates with intron retention reduction specifically found in SF3B1-mutated, but not in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibited augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restored Rloop formation,slowed down DNA replication forks and improved SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress is a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a new therapeutic target.
2024-02-22 | GSE220523 | GEO
Project description:Myelodysplastic syndromes (MDS) with mutated SF3B1 gene have many features including a favorable outcome that are distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we show that SF3B1-mutated MDS are characterized by a dramatically reduced R-loop formation predominating in gene bodies, which associates with intron retention reduction specifically found in SF3B1-mutated, but not in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibited augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restored Rloop formation,slowed down DNA replication forks and improved SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress is a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a new therapeutic target.
2024-02-22 | GSE220516 | GEO
Project description:SF3B1 is the most frequently mutated RNA splicing factor in cancer, including in ~25% of myelodysplastic syndromes (MDS) patients. SF3B1-mutated MDS, which is strongly associated with ringed sideroblast morphology, is characterized by ineffective erythropoiesis, leading to severe, often fatal, anemia. However, functional evidence linking SF3B1 mutations to the anemia described in MDS patients harboring this genetic aberration is weak, and the underlying mechanism is completely unknown. Using isogenic SF3B1 wild-type and mutant cell lines, normal human CD34 cells and MDS patient cells, we define a previously unrecognized role of the kinase MAP3K7, encoded by a known mutant SF3B1-targeted transcript, in controlling proper terminal erythroid differentiation, and show how MAP3K7 missplicing leads to the anemia characteristic of SF3B1-mutated MDS, although not to ringed sideroblast formation. We found that p38 MAPK is deactivated in SF3B1 mutant isogenic and patient cells and that MAP3K7 is an upstream positive effector of p38 MAPK. We demonstrate that disruption of this MAP3K7-p38 MAPK pathway leads to premature downregulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation, erythroid hyperplasia and ultimately apoptosis. Our findings thus define the mechanism leading to the severe anemia found in MDS patients harboring SF3B1 mutations.
2021-11-06 | GSE187356 | GEO
Project description:Myelodysplastic syndromes (MDS) with mutated SF3B1 gene have many features including a favorable outcome that are distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we show that SF3B1-mutated MDS are characterized by a dramatically reduced R-loop formation predominating in gene bodies, which tightly associates with reduced retention of introns specifically found in SF3B1-mutated, but not in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibited augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation, which were recapitulated in murine Sf3b1K700E/+ proerythroblasts. Importantly, R-loop formation was restored by histone deacetylase inhibition using SAHA/vorinostat, which improved Sf3b1K700E/+ erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress is a hallmark of SF3B1- mutated MDS ineffective erythropoiesis, which could be used as a new therapeutic target.
2024-02-22 | GSE220271 | GEO