The effects of mutant ASXL1 and BAP1 expression on hematopoietic cells
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA472882 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7212810_1.fastq.gz | Fastqsanger.gz | |||
| SRR7212810_2.fastq.gz | Fastqsanger.gz | |||
| SRR7212811_1.fastq.gz | Fastqsanger.gz | |||
| SRR7212811_2.fastq.gz | Fastqsanger.gz | |||
| SRR7212812_1.fastq.gz | Fastqsanger.gz |
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Project description:To identify target genes of mutant ASXL1 and BAP1 in hematopoietic cells, we performed RNA-seq using murine c-kit positive cells transduced with ASXL1-MT (MT) or ASXL1-MT-K351R (KR) together with vector or BAP1. Method：Murine c-kit positive bone marrow cells were transduced with ASXL1-MT (MT) or ASXL1-MT-K351R (KR) (coexpressing blastcidin resistant gene) together with vector or BAP1 (coexpressing puromycin resistant gene). After the selection with blasticidin and puromycin for three days, colony-forming cells were collected to extract RNA for RNA-seq analysis.
2018-05-25 | GSE114861 | GEO
Project description:ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here, we demonstrate that truncated ASXL1 proteins confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a hematopoietic precursor cell line resulted in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters bore both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes required the catalytic activity of BAP1, indicating these events were downstream consequences of H2AK119Ub erasure. In bone marrow precursors, truncated ASXL1-BAP1 expression cooperated with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. We propose that pathological ASXL1 mutations confer gain-of-function on the ASXL-BAP1 complex. ChIP-Seq for H2AK119Ub, H3K4me3, H3K27me3 on EML cells. RNA-Seq on EML cells expressing ASXL1(1-479)+BAP1 and control.
2015-03-11 | E-GEOD-65555 | biostudies-arrayexpress
Project description:ASXL1 is the obligate regulatory subunit of a deubiquitinase complex whose catalytic subunit is BAP1. Heterozygous mutations of ASXL1 that result in premature truncations are frequent in myeloid leukemias and Bohring-Opitz syndrome. Here, we demonstrate that truncated ASXL1 proteins confer enhanced activity on the ASXL1-BAP1 complex. Stable expression of truncated, hyperactive ASXL1-BAP1 complexes in a hematopoietic precursor cell line resulted in global erasure of H2AK119Ub, striking depletion of H3K27me3, selective upregulation of a subset of genes whose promoters bore both H2AK119Ub and H3K4me3, and spontaneous differentiation to the mast cell lineage. These outcomes required the catalytic activity of BAP1, indicating these events were downstream consequences of H2AK119Ub erasure. In bone marrow precursors, truncated ASXL1-BAP1 expression cooperated with TET2 loss-of-function to increase differentiation to the myeloid lineage in vivo. We propose that pathological ASXL1 mutations confer gain-of-function on the ASXL-BAP1 complex.
2015-03-11 | GSE65555 | GEO
Project description:The ASXL1 gene is the human homolog of the Drosophila Asx gene, a core subunit in the BAP1 histone H2A deubiquitinase complex. Mutations of ASXL1 occur in multiple myeloid neoplasms and are uniformly associated with poor prognosis. However, the molecular mechanism through which ASXL1 mutations alter BAP1 activity to drive leukemogenesis remains unclear. Here we demonstrate that cancer-associated frame-shift ASXL1 mutations, which were originally proposed to act as destabilizing loss-of-function mutations, in fact encode truncated stable gain-of-function proteins. Truncated ASXL1 protein stabilizes BAP1, enhances BAP1 complex recruitment to chromatin and promotes the expression of numerous leukemia associated genes. Chemical inhibition of BAP1 rescues these changes in gene expression in leukemic cells and inhibits tumor progression. This study represents a breakthrough advance in our understanding of the molecular mechanisms of ASXL1 mutations in leukemic pathogenesis and identifies small molecular inhibitors of BAP1 function as a potential targeted therapy for leukemia.
2021-03-07 | GSE166305 | GEO
Project description:To identify target genes of mutant ASXL1 (ASXL1-MT) and HHEX in hematopoietic cells, we performed RNA-seq using RUNX1-ETO expressing cord blood cells transduced with vector or ASXL1-MT together with vector or HHEX.
2020-06-09 | GSE147654 | GEO
Project description:Histone H3K4 monomethyltransferases MLL3 and MLL4 contain a set of uncharacterized PHD fingers. By structural and biochemical assays, we found a novel function of the PHD2 and PHD3 (PHD2/3) fingers of MLL3 and MLL4, revealing their direct binding to the conserved MBH (MLL binding helix) region of ASXL1/2, components of the Polycomb repressive PR-DUB complex. In mouse embryonic stem cells, we observed that BAP1, the catalytic subunit of the PR-DUB complex, physically interacts with MLL4 in an ASXL1/2 MBH-dependent manner. Genomic studies demonstrate that the ASXL1/2 MBH is required for BAP1 binding on active enhancers and suggest that MLL4 facilitates BAP1 binding on active enhancers through ASXL1/2 MBH.
2024-04-30 | GSE248027 | GEO
Project description:Somatic mutations of ASXL1 are frequently detected in age-related clonal hematopoiesis (CH). However, how ASXL1 mutations drive CH remains elusive. Using knockin (KI) mice expressing a C-terminally truncated form of ASXL1-mutant (ASXL1-MT), we examined the influence of ASXL1-MT on physiological aging in hematopoietic stem cells (HSCs). HSCs expressing ASXL1-MT display competitive disadvantage after transplantation. Nevertheless, in genetic mosaic mouse model, they acquire clonal advantage during aging, recapitulating CH in humans. Mechanistically, ASXL1-MT cooperates with BAP1 to deubiquitinate and activate AKT. Overactive Akt/mTOR signaling induced by ASXL1-MT results in aberrant proliferation and dysfunction of HSCs associated with age-related accumulation of DNA damage. Treatment with an mTOR inhibitor rapamycin ameliorates aberrant expansion of the HSC compartment as well as dysregulated hematopoiesis in aged ASXL1-MT KI mice. Our findings suggest that ASXL1-MT provokes dysfunction of HSCs, whereas it confers clonal advantage on HSCs over time, leading to the development of CH.
2021-02-08 | MSV000086816 | MassIVE
Project description:The effects of expression of mutant ASXL1 and HHEX on hematopoietic cells
| PRJNA615886 | ENA
Project description:Additional Sex Combs Like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. Here we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphologic dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. ChIP-seq analysis demonstrated opposing effects of wildtype and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.
2018-02-28 | GSE111067 | GEO
Project description:We report the genome wide binding sites of BAP1, HCF1 and OGT in bone marrow derived macrophages. De-ubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with increased risk of mesothelioma and uveal melanoma. Somatic BAP1 mutations occur in various malignancies. We show that mouse Bap1 gene deletion is lethal during embryogenesis, but systemic or hematopoietic-restricted deletion in adults recapitulates features of human myelodysplastic syndrome (MDS). Knockin mice expressing BAP1 with a 3xFlag tag revealed that BAP1 interacts with host cell factor–1 (HCF-1), O-linked N-acetylglucosamine transferase (OGT), and the polycomb group proteins ASXL1 and ASXL2 in vivo. OGT and HCF-1 levels were decreased by Bap1 deletion, indicating a critical role for BAP1 in stabilizing these epigenetic regulators. Human ASXL1 is mutated frequently in chronic myelomonocytic leukemia (CMML) so an ASXL/BAP1 complex may suppress CMML. A BAP1 catalytic mutation found in a MDS patient implies that BAP1 loss of function has similar consequences in mice and humans. For BAP1, bone marrow derived macrophages were used differentiated from bone marrow cells of BAP1-3X Flag Tagged KI mice we generated. For OGT and HCF1, bone marrow derived macrophages were used from BAP1 WT mice.
2012-11-07 | E-GEOD-40723 | biostudies-arrayexpress