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Mutant U2AF1-Induced Alternative Splicing of H2afy (macroH2A1) Regulates B-Lymphopoiesis in Mice

ABSTRACT: Acquired spliceosome gene mutations are among the most common genetic alterations in myelodysplastic syndromes (MDS). Here we present evidence that H2AFY(macroH2A1), a histone H2A variant, is a functional target that is alternatively spliced by mutant U2AF1(S34F), a spliceosome gene. Expression of H2AFY1.1, a H2AFY splice-isoform that is reduced by U2AF1(S34F) expression, rescues the reduction in B-cells observed in U2AF1(S34F) mice. Human MDS samples with U2AF1 mutations have a similar reduction in B-cells. Collectively, our data suggest that altered splicing of H2AFY contributes to MDS pathogenesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE125118 | GEO | 2021/08/31

REPOSITORIES: GEO

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RNA sequencing of erythroid and granulomonocytic colonies differentiated from transduced bone marrow CD34+ cells expressing U2AF1 S34F mutation, U2AF1 wild-type or empty vector control

Project description:Mutations of the splicing factor U2AF1 are frequent in the myeloid malignancy myelodysplastic syndromes (MDS) and in other cancers. Patients with MDS suffer from peripheral blood cytopenias, including anemia, and increasing bone marrow blasts. We investigated the impact of the common U2AF1 S34F mutation on cellular function and mRNA splicing in the main cell lineages affected in MDS. We demonstrated that U2AF1 S34F expression in human hematopoietic progenitors impairs erythroid differentiation, and skews granulomonocytic differentiation towards granulocytes. RNA-sequencing of erythroid and granulomonocytic colonies revealed that U2AF1 S34F induced a higher number of cassette exon splicing events in granulomonocytic than erythroid cells, and altered mRNA splicing of many transcripts (expressed in both cell types) in a lineage-specific manner. The introduction of isoform changes identified in the target genes H2AFY and STRAP into hematopoietic progenitors recapitulated phenotypes associated with U2AF1 S34F expression in erythroid and/or granulomonocytic cells, suggesting a causal link. Importantly, we provided evidence showing that isoform modulation of the U2AF1 S34F target genes H2AFY and STRAP rescues the erythroid differentiation defect in U2AF1 S34F MDS cells, raising the possibility of using splicing modulators therapeutically. These data have critical implications for understanding MDS phenotypic heterogeneity, and for the development of new targeted therapies.

2017-04-25 | GSE94153 | GEO

RNA sequencing of mouse bone marrow cells from transgenic mice following short term induction of mutant U2AF1(S34F) or U2AF1(WT) expression concurrent with sudemycin D6 (or vehicle) treatment in vivo

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2016-11-15 | GSE89834 | GEO

RNA-Seq data from U2 small nuclear RNA auxiliary factor 1 (U2AF1)-S34F and WT SKM-1 cells

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Mutant U2AF1-Induced Alternative Splicing of H2afy (macroH2A1) Regulates B-Lymphopoiesis in Mice

Project description:Mutant U2AF1-Induced Alternative Splicing of H2afy (macroH2A1) Regulates B-Lymphopoiesis in Mice

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Identification of differentially spliced genes by wild type or S34F mutation of U2AF1

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2015-11-01 | E-GEOD-66553 | biostudies-arrayexpress

RNA sequencing of common myeloid progenitors following short term induction of mutant U2AF1(S34F) expression in transgenic mice

Project description:Mutations in the splicing factor gene U2AF1 have been found in the bone marrow of patients with myelodysplastic syndrome and acute myeloid leukemia, as well as in other cancers. To study the effects of mutant U2AF1(S34F) expression on hematopoiesis and pre-mRNA splicing in hematopoietic cells, we generated two inducible transgenic mouse lines expressing either mutant U2AF1(S34F) or U2AF1(wildtype, WT) as control. We performed strand-specific transcriptome sequencing on bone marrow common myeloid progenitor cells from U2AF1(S34F) and U2AF1(WT)-expressing mice to examine the pre-mRNA splicing changes associated with expression of mutant U2AF1(S34F). Donor-derived common myeloid progenitor cells from mice transplanted with U2AF1(S34F)/rtTA or U2AF1(WT)/rtTA bone marrow were sorted by flow cytometry, and RNA was extracted for transcriptome analysis. Ribosomal RNA was depleted prior to strand-specific RNA sequencing (TruSeq stranded library production, followed by 2 x 100bp paired-end sequencing performed on the HiSeq2000 platform from Illumina). Three samples were sequenced per genotype (n=3), and each sample was composed of bone marrow from 4-5 mice pooled. Reads were aligned to the mouse mm9 reference genome using TopHat (version 2.0.8), and we performed all subsequent analyses in R.

2015-05-11 | E-GEOD-66793 | biostudies-arrayexpress

Multi-omics analysis of RNA binding, splicing and turnover alterations induced by mutant U2AF1 in myeloid malignancies.

Project description:Splicing factor mutations are common among cancers, recently emerging as drivers of myeloid malignancies. U2AF1 carries hotspot mutations in its RNA binding motifs; yet how they affect splicing and promote cancer remains unclear. The U2AF1/U2AF2 heterodimer is critical for 3’ splice site (3’SS) definition. To specifically unmask changes in U2AF1 function in vivo, we developed a crosslinking and immunoprecipitation procedure detecting contacts between U2AF1 and the 3’SS AG at single-nucleotide resolution (fractionated eCLIP-seq or freCLIP-seq). Our data reveal that U2AF1 S34F and Q157R mutants establish new 3’SS contacts at -3 and +1 nucleotides, respectively. These effects compromise U2AF2-RNA interactions, resulting predominantly in intron retention and exon exclusion. Integrating RNA binding (eCLIP-seq and freCLIP-seq), splicing (RNA-seq) and turnover (TimeLapse-seq or TL-seq) data, we predicted that U2AF1 mutations directly affect stress granule components. Remarkably, U2AF1-mutant cell lines and patient-derived MDS/AML blasts displayed a heightened stress granule response, pointing to a novel role for biomolecular condensates in adaptive oncogenic strategies. Keywords: splicing, RNA binding, U2AF1, U2AF2, S34F, Q157R, hotspot mutations, 3'SS, 3' splice site, myeloid malignancies, eCLIP, freCLIP, RNA-seq, RNA turnover, TimeLapse-seq, TL-seq, RNA granules, stress granules, stress response, biomolecular condensates, MDS, AML

2022-03-17 | GSE195620 | GEO

U2AF1 is a haplo-essential gene required for hematopoietic cancer cell survival in mice

Project description:Somatic mutations in the spliceosome gene U2AF1 are common in patients with myelodysplastic syndromes. U2AF1 mutations that code for the most common amino acid substitutions are always heterozygous, and the retained wild-type allele is expressed, suggesting that mutant hematopoietic cells may require the residual wild-type allele to be viable and cause disease. We show that hematopoiesis and RNA splicing in U2af1 heterozygous knock-out mice was similar to control mice, but that deletion of the wild-type allele in U2AF1 (S34F) heterozygous mutant expressing hematopoietic cells (i.e., hemizygous mutant) was lethal. These results confirm that U2AF1 mutant hematopoietic cells are dependent on the expression of wild-type U2AF1 for survival in vivo and that U2AF1 is a haplo-essential cancer gene. Mutant U2AF1 (S34F) expressing cells were also more sensitive to reduced, but not absent, expression of wild-type U2AF1 than non-mutant cells. Furthermore, mice transplanted with leukemia cells expressing mutant U2AF1 had significantly reduced tumor burden and improved survival after the wild-type U2af1 allele was deleted compared to when it was not deleted. These results suggest that selectively targeting the wild-type U2AF1 allele in heterozygous mutant cells could induce cancer cell death and be a therapeutic strategy for patients harboring U2AF1 mutations.

2021-09-23 | GSE152213 | GEO

RNA sequencing of common myeloid progenitors following short term induction of mutant U2AF1(S34F) expression in transgenic mice

2015-05-11 | GSE66793 | GEO

Whole transcriptome splicing analysis in isogenic lung epithelial and adenocarcinoma cell lines with or without a recurrent splicing factor mutation, U2AF1 (S34F)

Project description:The splicing factor gene, U2AF1, is recurrently mutated in a variety of human cancers, including lung adenocarcinomas. The most frequent U2AF1 mutant, U2AF1 p.Ser34Phe (S34F), induces specific changes in pre-mRNA splicing, but it is unclear how these splicing changes are regulated. We have used genomic editing methods to modify the U2AF1 gene locus in an immortalized human bronchial epithelial cell line (HBEC3kt) and in human lung adenocarcinoma cells with pre-existing U2AF1 alleles, creating a U2AF1 S34F allele in the endogenous locus of HBEC3kts and inactivating U2AF1 S34F alleles in two lung adenocarcinoma cell lines (H441 and HCC78). By comparing global splicing alterations in these isogenic pairs of cell lines, we have identified many splicing alterations that are associated with the U2AF1 S34F mutation. Further, by decreasing the levels of wild-type U2AF1 in the isogenic HBEC3kt cells, we show that the magnitude of mutant-associated splicing is proportional to the ratio of S34F:WT gene products. This observation suggest that wild-type U2AF1 is a negative regulator of splicing alterations induced by U2AF1 S34F.

2016-09-30 | GSE80136 | GEO

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