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Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE220529 | GEO | 2024/02/22

REPOSITORIES: GEO

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Similar Datasets

Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation.

Project description:Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we find that SF3B1-mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.

| S-EPMC11001894 | biostudies-literature

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_CMNhuman]

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

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_erythroHuman]

2024-02-22 | GSE220523 | GEO

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_G1EER]

2024-02-22 | GSE220516 | GEO

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [DRIP-seq]

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

DNA Replication Stress Due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation

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

DNA Replication Stress Due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation

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

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation

Project description:Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation

| PRJNA910130 | ENA

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_G1EER]

Project description:Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_G1EER]

| PRJNA910113 | ENA

Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_erythroHuman]

Project description:Accelerated DNA replication fork speed due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation [RNAseq_erythroHuman]

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