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Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [TRIBE-seq]

ABSTRACT: Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [TRIBE-seq]

PROVIDER: PRJNA1011321 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25845455_1.fastq.gz	Fastqsanger.gz
	SRR25845455_2.fastq.gz	Fastqsanger.gz
	SRR25845456_1.fastq.gz	Fastqsanger.gz
	SRR25845456_2.fastq.gz	Fastqsanger.gz
	SRR25845457_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [TRIBE-seq]

Project description:Mutations in the RNA splicing factor SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing but therapeutic means to correct this mis-splicing do not exist. Here we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SUGP1, a G-patch protein recently implicated in SF3B1 mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1 splicing defects and was sufficient to improve hematopoiesis in SF3B1 mutant mouse and human cells. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and the therapeutic impact of correcting aberrant splicing in SF3B1 mutant cancers.

2023-09-01 | GSE242093 | GEO

Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [RNA-seq]

2023-09-01 | GSE242092 | GEO

Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [RNA-Seq 2]

2024-03-20 | GSE262021 | GEO

Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations

Project description:Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations

| PRJNA1011318 | ENA

GPATCH8 modulates mutant SF3B1 mis-splicing and pathogenicity in hematologic malignancies

Project description:Mutations in the RNA splicing factor gene SF3B1 are common across hematologic and solid cancers and result in widespread alterations in splicing, but therapeutic means to correct this mis-splicing do not exist. Here, we utilize synthetic introns uniquely responsive to mutant SF3B1 to identify trans factors required for aberrant mutant SF3B1 splicing activity. This revealed the G-patch domain-containing protein GPATCH8 as required for mutant SF3B1-induced splicing alterations and impaired hematopoiesis. GPATCH8 is involved in quality control of branchpoint selection, interacts with the RNA helicase DHX15, and functionally opposes SUGP1, a G-patch protein recently implicated in SF3B1-mutant diseases. Silencing of GPATCH8 corrected one-third of mutant SF3B1-dependent splicing defects and was sufficient to improve dysfunctional hematopoiesis in SF3B1-mutant mouse and primary human progenitors. These data identify GPATCH8 as a novel splicing factor required for mis-splicing by mutant SF3B1 and highlight the therapeutic impact of correcting aberrant splicing in SF3B1-mutant cancers.

2024-04-10 | PXD051128 | Pride

Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [RNA-seq]

Project description:Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [RNA-seq]

| PRJNA1011320 | ENA

Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [RNA-Seq 2]

Project description:Synthetic Introns Identify GPATCH8 as Required for Mis-splicing by SF3B1 Mutations [RNA-Seq 2]

| PRJNA1090048 | ENA

Mis-splicing of mitotic regulators sensitizes SF3B1-mutated human HSCs to CHK1 inhibition [scRNA-seq]

Project description:Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs remain unclear. Here, we identify the mis-splicing program in human HSCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells. Mutant SF3B1 induced pervasive mis-splicing and reduced expression of genes regulating mitosis in single cell transcriptomics, critically BUBR1 and CDC27, leading to altered differentiation and delayed G2/M progression. Mutant SF3B1 mis-splicing or reduced expression of BUBR1 and CDC27 was sufficient to delay G2/M transit, leading to activation of CHK1, sensitizing cells to CHK1 inhibition. Clinical CHK1 inhibitor prexasertib selectively targeted SF3B1-mutant HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition.

2024-05-29 | GSE263300 | GEO

Mis-splicing of mitotic regulators sensitizes SF3B1-mutated human HSCs to CHK1 inhibition [RNA-seq]

2024-05-29 | GSE263299 | GEO

Coordinated mis-splicing of TMEM14C and ABCB7 causes ring sideroblast formation in SF3B1-mutant myelodysplastic syndrome

Project description:Purpose: Mutant SF3B1 is near universally associated with MDS-RS but the exact mechanism of how mutant-SF3B1 induces ring sideroblast formation is unclear. Methods: iPSC samples were differentiated from 5F-HPC derived from MDS-RS patient iPSCs. CD34+ progenitors were isolated using the CD34 enrichment kit (Miltenyi). CD34-CD71+GlyA- pro-erythroblasts were isolated by flow sorting on day 4. CD71+GlyA+ erythroblasts were isolated by flow sorting on day 9. Libraries with DNA fragments of ~300bp were selected using AMPure XP bead purification. Purified libraries were sequenced on an Illumina HiSeq 2000 using paired-end, 50 bp reads. Mis-splicing analysis was performed as described in Inoue et al. 2019. Results: Mis-splicing analysis reveals ~100 genes that are strongly mis-spliced (>40%) by mutant SF3B1 during erythroid differentiation. We identify that mis-splicing of TMEM14C and ABCB7 contribute to RS formation in mutant SF3B1 cells. Conclusion: Our iPS derived mutant SF3B1MDS-RS in vitro model is the first demonstration of a cell line that recapitulates mis-splicing, erythroid differentiation, and ring sideroblast formation.

2021-11-29 | GSE189546 | GEO

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