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RNA-seq of LSK isolated from U2af1 mutant, Tet2 mutant and U2af1/Tet2 double mutant against wild-type controls.

ABSTRACT: To investigate the transcriptome of hematopoietic stem and progenitor cells (Lin-Sca-1+c-kit+) carrying alterations in splicing factors and/or epigenetic regulators related with the pathogenesis of myelodysplastic syndromes.

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Mus musculus

SUBMITTER: Alejandra Sanjuan Pla

PROVIDER: E-MTAB-10486 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes.

Martínez-Valiente Cristina C Garcia-Ruiz Cristian C Rosón Beatriz B Liquori Alessandro A González-Romero Elisa E Fernández-González Raúl R Gómez-Redondo Isabel I Cervera José J Gutiérrez-Adán Alfonso A Sanjuan-Pla Alejandra A

International journal of molecular sciences 20210628 13

Mutations in splicing factors are recurrent somatic alterations identified in myelodysplastic syndromes (MDS) and they frequently coincide with mutations in epigenetic factors. About 25% of patients present concurrent mutations in such pathways, suggesting a cooperative role in the pathogenesis of MDS. We focused on the splicing factor U2AF1 involved in the recognition of the 3' splice site during pre-mRNA splicing. Using a CRISPR/Cas9 system, we created heterozygous mice with a carboxy-terminal ...[more]

PMID: 34203454

Similar Datasets

RNA-seq of LSK isolated from Zrsr2 mutant, Tet2 mutant and Zrsr2/Tet2 double mutant against wild-type controls

Project description:To describe the transcriptome of hematopoietic stem and progenitor cells ( Lin-Sca-1+c-kit+ ) carrying alterations in minor spliceosome factors and/or epigenetic regulators related to the pathogenesis of myelodysplastic syndromes.

2022-08-31 | E-MTAB-10481 | biostudies-arrayexpress

Context Dependent Effects of Ascorbic Acid Treatment in TET2 Mutant Myeloid Neoplasia

Project description:Loss-of-function TET2 mutations (TET2MT) are common in myeloid neoplasia. TET2, a DNA dioxygenase, requires 2-oxoglutarate and Fe(II) to oxidize 5-methylcytosine. TET2MT thus result in hypermethylation and transcriptional repression. Ascorbic acid (AA) increases dioxygenase activity by facilitating Fe(III)/Fe(II) redox reaction and may alleviate some biological consequences of TET2MT by restoring dioxygenase activity. Here, we report the utility of AA in the prevention of TET2MT MN, clarify the mechanistic underpinning of the TET2-AA interactions, and demonstrate that the ability of AA to restore TET2 activity in cells depends on N- and C-terminal lysine acetylation and nature of TET2MT. Consequently, pharmacologic modulation of acetyltransferases and histone deacetylases may regulate TET dioxygenase-dependent AA effects. Thus, our study highlights the contribution of factors that may enhance or attenuate AA effects on TET2 and provides a rationale for novel therapeutic approaches including combinations of AA with class I/II HDAC inhibitor or sirtuin activators in TET2MT leukemia.

2020-09-09 | PXD020550 | Pride

ZRSR2 mutant myelodysplastic syndromes

Project description:ZRSR2 mutant myelodysplastic syndromes

| PRJNA671388 | ENA

ZRSR2 mutant myelodysplastic syndromes

Project description:ZRSR2 mutant myelodysplastic syndromes

| PRJNA671387 | ENA

Tet2 loss leads to increased hematopoietic stem cell self-renewal and myeloid transformation

Project description:Recurrent somatic mutations in TET2 and in other genes that regulate the epigenetic state have been identified in patients with myeloid malignancies and in other cancers. However, the in vivo effects of Tet2 loss have not been delineated. We report here that Tet2 loss leads to increased stem-cell self-renewal and to progressive stem cell expansion. Consistent with human mutational data, Tet2 loss leads to myeloproliferation in vivo, notable for splenomegaly and monocytic proliferation. In addition, haploinsufficiency for Tet2 confers increased self-renewal and myeloproliferation, suggesting that the monoallelic TET2 mutations found in most TET2-mutant leukemia patients contribute to myeloid transformation. This work demonstrates that absent or reduced Tet2 function leads to enhanced stem cell function in vivo and to myeloid transformation. These studies show that a ubiquitin ligase-substrate pair can orchestrate the molecular program of HSC differentitiation Gene expression profiles from WT and Tet2-/- sorted LSK and myeloid progenitors (CMP and GMP) were compared using genome wide mRNA expression profiling by Affymetrix genechip arrays (Mouse 430 2.0) and key targets were validated by chromatin immunoprecipitation experiments.

2011-07-01 | E-GEOD-27816 | biostudies-arrayexpress

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

Project description: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.

2021-08-31 | GSE125118 | GEO

TET2 binding protein of human colon cancer cell SW480-SW620

Project description:This project was aimed to identify proteins interatcted with TET2 and the differences between SW480 and SW620.

2023-10-24 | PXD020080 | Pride

Aberrant Alternative Splicing in U2af1/Tet2 Double Mutant Mice Contributes to Major Hematological Phenotypes.

Project description:Mutations in splicing factors are recurrent somatic alterations identified in myelodysplastic syndromes (MDS) and they frequently coincide with mutations in epigenetic factors. About 25% of patients present concurrent mutations in such pathways, suggesting a cooperative role in the pathogenesis of MDS. We focused on the splicing factor U2AF1 involved in the recognition of the 3' splice site during pre-mRNA splicing. Using a CRISPR/Cas9 system, we created heterozygous mice with a carboxy-terminal truncated U2af1 allele (U2af1mut/+), studied the U2af1mut/+ hematopoietic system, and did not observe any gross differences in both young (12-13 weeks) and old (23 months) U2af1mut/+ mice, except for a reduction in size of approximately 20%. However, hematopoietic stem/progenitor cells lacked reconstitution capacity in transplantation assays and displayed an aberrant RNA splicing by RNA sequencing. We also evaluated U2af1mut/+ in conjunction with Tet2-deficiency. Novel double mutant U2af1mut/+Tet2-/- mice showed increased monogranulocytic precursors. Hematopoietic stem/progenitor cells were also enhanced and presented functional and transcriptomic alterations. Nonetheless, U2af1mut/+Tet2-/- mice did not succumb to MDS disease over a 6-month observation period. Collectively, our data suggest that cooperation between mutant U2af1 and Tet2 loss is not sufficient for MDS initiation in mice.

| S-EPMC8269301 | biostudies-literature

RNA-seq of LSK isolated from U2af1 mutant, Tet2 mutant and U2af1/Tet2 double mutant against wild-type controls.

Project description:RNA-seq of LSK isolated from U2af1 mutant, Tet2 mutant and U2af1/Tet2 double mutant against wild-type controls.

| PRJEB44970 | ENA

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

Project description:Mutations in spliceosome genes occur in the bone marrow of approximately 50% of patients with myelodysplastic syndromes (MDS), with mutations in the splicing factor gene U2AF1 found in ~11% of MDS patients. We hypothesized that cells harboring a spliceosome gene mutation would have increased sensitivity to further perturbation of the spliceosome by splicing modulator drugs. To examine the effects of the splicing modulator drug sudemycin D6 on primary hematopoietic cells expressing mutant U2AF1(S34F), we treated transgenic mice expressing either mutant U2AF1(S34F) or U2AF1(wildtype, WT) concurrently with 5 days of sudemycin D6 treatment in vivo. We harvested bulk bone marrow cells 18 hours after the last day of treatment and performed strand-specific transcriptome sequencing to examine the cumulative pre-mRNA splicing changes associated with both mutant U2AF1 expression and sudemycin D6 treatment.

2016-11-15 | GSE89834 | GEO

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