Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Intragenic Epigenetic Deregulation by IDH2 Mutations Synergizes with SRSF2 Mutations Causing Mis-splicing of Key Transcriptional Regulators [RNA-seq]

ABSTRACT: Genes impacting DNA methylation (DNAme), like IDH2, are frequently co-mutated with splicing factors, like SRSF2, in acute myeloid leukemia (AML). These co-occurring mutations are associated with more aggressive phenotypes but the underlying molecular mechanisms remain elusive. To address this gap, we profiled wild-type, IDH2R140Q or SRSF2P95 single-mutants and IDH2R140Q/SRSF2P95 double-mutant AMLs at a deep resolution level. We find a unique set of mis-spliced genes and differentially methylated CpGs in double-mutants. Mis-spliced exons are enriched in CCNG splicing enhancers and in the corresponding DNAme changes. Using a machine-learning model, we can accurately predict exon inclusion levels from proximal CpGs. These CpGs are more likely to overlap with footprints of RNA-binding and chromatin-modifying complexes but not transcription factors. We also report unique gene expression profiles associated with each genotype; however, the differentially expressed genes do not overlap with mis-spliced transcripts. Instead, the mis-spliced genes encode for proteins that interact with the gene regulatory complexes that control the expression of these differentially expressed genes. Thus, we propose a mechanism where synergism between aberrant DNAme and splicing leads to the mis-splicing of key components in gene regulatory complexes, thus resulting in the aberrant gene expression profiles characteristic of these AMLs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE280581 | GEO | 2025/11/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Intragenic Epigenetic Deregulation by IDH2 Mutations Synergizes with SRSF2 Mutations Causing Mis-splicing of Key Transcriptional Regulators [BiSulfite-seq]

Project description:Genes impacting DNA methylation (DNAme), like IDH2, are frequently co-mutated with splicing factors, like SRSF2, in acute myeloid leukemia (AML). These co-occurring mutations are associated with more aggressive phenotypes but the underlying molecular mechanisms remain elusive. To address this gap, we profiled wild-type, IDH2R140Q or SRSF2P95 single-mutants and IDH2R140Q/SRSF2P95 double-mutant AMLs at a deep resolution level. We find a unique set of mis-spliced genes and differentially methylated CpGs in double-mutants. Mis-spliced exons are enriched in CCNG splicing enhancers and in the corresponding DNAme changes. Using a machine-learning model, we can accurately predict exon inclusion levels from proximal CpGs. These CpGs are more likely to overlap with footprints of RNA-binding and chromatin-modifying complexes but not transcription factors. We also report unique gene expression profiles associated with each genotype; however, the differentially expressed genes do not overlap with mis-spliced transcripts. Instead, the mis-spliced genes encode for proteins that interact with the gene regulatory complexes that control the expression of these differentially expressed genes. Thus, we propose a mechanism where synergism between aberrant DNAme and splicing leads to the mis-splicing of key components in gene regulatory complexes, thus resulting in the aberrant gene expression profiles characteristic of these AMLs.

2025-11-26 | GSE280562 | GEO

Distinct and convergent consequences of splice factor mutations in myelodysplastic syndromes

Project description:Myelodysplastic syndromes (MDS) are characterized by recurrent somatic alterations often affecting components of RNA splicing machinery. Mutations of splice factors SF3B1, SRSF2, ZRSR2 and U2AF1 occur in >50% of MDS. To assess the impact of spliceosome mutations on splicing and to identify common pathways/genes affected by distinct mutations, we performed RNA-sequencing of 24 MDS bone marrow samples harboring spliceosome mutations (including hotspot alterations of SF3B1, SRSF2 and U2AF1; small deletions of SRSF2 and truncating mutations of ZRSR2), and devoid of other common co-occurring mutations. We uncover the landscape of splicing alterations in each splice factor mutant MDS and demonstrate that SRSF2 deletions cause highest number of splicing alterations compared with other spliceosome mutations. Although the mis-spliced events observed in different splice factor mutations were largely non-overlapping, a subset of genes, including EZH2, were aberrantly spliced in multiple mutant groups. Pathway analysis revealed that the mis-spliced genes in different mutant groups were enriched in RNA splicing and transport as well as several signaling cascades, suggesting converging biological consequences downstream of distinct spliceosome mutations.

2019-11-07 | GSE128429 | GEO

Epigenetic identity in AML is mostly dependent on disruption of non-promoter regulatory elements and reveals potentially antagonistic effects of mutations in epigenetic modifiers [mouse]

Project description:Aberrant DNA methylation of gene promoters is a hallmark of AML. To define more precisely how cytosine methylation is redistributed in AML, we performed base-pair resolution methylome sequencing in 119 patients. We find that leukemic DNA methylation patterning is tightly linked to somatic mutations and primarily driven by regulatory elements outside of promoters and by CpG shores as opposed to CpG islands. Active enhancers displayed much stronger focal differential methylation than promoters and were generally aberrantly hypomethylated except in IDH2 mutant and CEBPA silenced AMLs. AMLs with dominant hypermethylation feature greater epigenetic disruption of promoters. Those with dominant hypomethylation, such as DNMT3A mutated AMLs, display greater disruption of distal and intronic regions. IDH mutant AMLs manifest profound hypermethylation whereas DNMT3A mutant AMLs manifest profound hypomethylation of a different set of CpGs. In striking contrast, AMLs with co-occurring IDH1 and DNMT3A mutations exhibited epigenetic antagonism in which most CpGs affected by either mutation alone were no longer affected in the double mutant cases.

2017-04-28 | GSE96744 | GEO

Epigenetic identity in AML is mostly dependent on disruption of non-promoter regulatory elements and reveals potentially antagonistic effects of mutations in epigenetic modifiers [human]

Project description:Aberrant DNA methylation of gene promoters is a hallmark of AML. To define how cytosine methylation is redistributed in AML more precisely we performed base-pair resolution methylome sequencing in 119 patients. We find that leukemic DNA methylation patterning is tightly linked to somatic mutations and primarily driven by regulatory elements outside of promoters and by CpG shores as opposed to CpG islands. Active enhancers displayed much stronger focal differential methylation than promoters and were generally aberrantly hypomethylated except in IDH2 mutant and CEBPA silenced AMLs. AMLs with dominant hypermethylation feature greater epigenetic disruption of promoters. Those with dominant hypomethylation, such as DNMT3A mutated AMLs, display greater disruption of distal and intronic regions. IDH mutant AMLs manifest profound hypermethylation whereas DNMT3A mutant AMLs manifest profound hypomethylation of a different set of CpGs. In striking contrast, AMLs with co-occurring IDH1 and DNMT3A mutations exhibited epigenetic antagonism in which most CpGs affected by either mutation alone were no longer affected in the double mutant cases. These patients featured a unique gene expression profile featuring deregulated expression of RAS pathway that was not linked to DNA methylation.

2017-04-19 | GSE86952 | 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

Mis-splicing derived neoantigens and cognate T cell receptors in splicing factor mutant leukemias

Project description:Mutations in RNA splicing factors are prevalent across cancers and generate recurrently mis-spliced mRNA isoforms. Here we identified a series of bona fide neoantigens translated from highly stereotyped splicing alterations promoted by neomorphic, leukemia-associated somatic mutations in the splicing machinery. We utilized feature-barcoded peptide-MHC dextramers to isolate neoantigen-specific T cell receptors (TCR) from both healthy donors and patients with leukemia. While circulating neoantigen-specific CD8+ T cells were identified in patients with active disease, they were dysfunctional with reduced inflammatory response gene signatures. In contrast, donor CD8+ T cells with tumor-reactive TCRs were present following curative allogeneic hematopoietic cell transplant. T cells engineered with TCRs recognizing an SRSF2 mutant-induced neoantigen in CLK3 resulted in specific recognition and cytotoxicity of SRSF2 mutant leukemia. These data identify RNA mis-splicing derived neoantigens and neoantigen-specific TCRs across patients and provide proof-of-concept to genetically redirect T cells to public mis-splicing derived neoantigens in myeloid leukemias.

2024-05-22 | GSE268157 | GEO

Transcriptome characterization of chronic myeloid leukemia by RNA sequencing

Project description:To determine differentially expressed and spliced transcripts in chronic myeloid leukemia, a high throughput RNA-sequencing (RNA-seq) analysis of ten CML specimens and five normal peripheral blood samples was performed. Thousands of differentially expressed genes between CML and normal control were detected, including genes involved in ribosome and signaling pathway. Splicing alterations analysis performed by an independently developed algorithm reveals that intron retention was the most frequent alternative splicing (AS) events in all the samples. Functional groups of differentially spliced genes most highly correlated with disease phase was (blast crisis relative to chronic phase) included spliceosome and nucleotide excision repair (NER), suggesting that genes involved in these processes may have a major contribution to CML progression by affecting splicing factors and DNA damage and repair as a consequence of mis-splicing.

2020-05-06 | GSE100026 | GEO

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