RNA sequencing of zebrafish asxl1+/+ and asxl1-/-
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA596232 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10721215_1.fastq.gz | Fastqsanger.gz | |||
| SRR10721215_2.fastq.gz | Fastqsanger.gz | |||
| SRR10721216_1.fastq.gz | Fastqsanger.gz | |||
| SRR10721216_2.fastq.gz | Fastqsanger.gz | |||
| SRR10721217_1.fastq.gz | Fastqsanger.gz |
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Project description:ASXL1 gene is one of the most frequently mutated genes in malignant myeloid diseases. In patients, ASXL1 mutations are usually heterozygous frameshift or non-sense mutations leading to C-terminal truncation. Here, we generated an endogenous C-terminal truncated Asxl1 mutant in zebrafish which is more comparable to human malignant leukemia patients. Our data showed that at embryonic stage, neutrophil differentiation was explicitly blocked in our mutant. To understand the basis for the impairment of neutrophil differentiation in zebrafish asxl1 mutants, we performed RNA-seq of asxl1 mutants at 3dpf and their littermate controls. Similar with the phenotype we observed, the expression of neutrophil markers were all included in down-regulated genes. Nonetheless, the expression of myeloid progenitor marker and macrophage marker were not impaired in asxl1 mutants. We also found inflammatory cytokine and matrix metalloproteinases were upregulated after mutated asxl1. It suggests that neutrophil deficiency may stimulate the expression of some inflammatory cytokines and enhances the inflammatory responds. Therefore, transcriptome analysis mainly represented the disruption of neutrophil development.
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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:Recurrent somatic ASXL1 mutations occur in patients with myelodysplasia (MDS), myeloproliferative neoplasms (MPN), and acute myeloid leukemia (AML), and are associated with adverse outcome. Despite the genetic and clinical data implicating ASXL1 mutations in myeloid malignancies, the mechanisms of transformation by ASXL1 mutations are not understood. Here we identify that ASXL1 mutations result in loss of PRC2-mediated histone H3 lysine 27 (H3K27) tri-methylation. Through integration of microarray data with genome-wide histone modification ChIP-Seq data we identify targets of ASXL1 repression including the posterior HOXA cluster that is known to contribute to myeloid transformation. We demonstrate that ASXL1 associates with the Polycomb repressive complex 2 (PRC2), and that loss of ASXL1 in vivo collaborates with NRASG12D to promote myeloid leukemogenesis. To assess the genome-wide effects of ASXL1 loss on chromatin state we performed chromatin immunoprecipitation followed by next generation sequencing (CHIP-seq) for histone modifications known to be associated with PcG (histone H3 lysine 27 trimethylation (H3K27me3)) or TxG activity (histone H3 lysine 4 trimethylation (H3K4me3)) in UKE1 cells expressing empty vector (EV) or 2 independent validated shRNAs for ASXL1. This Series represents the ChIP-Seq data (not the microarray data referenced in the summary above). The related micorarray data are available in GEO as GSE38692.
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Project description:Mutations in the gene Additional Sex-Combs Like 1 (ASXL1) are recurrent in myeloid malignancies as well as the pre-malignant condition clonal hematopoiesis, where they are universally associated with poor prognosis. An epigenetic regulator, ASXL1 canonically directs the deposition of H3K27me3 via the polycomb repressive complex 2. However, its precise role in myeloid lineage maturation is incompletely described. We utilized single cell RNA sequencing (scRNA-seq) on a murine model of hematopoietic-specific ASXL1 deletion and identified a specific role for ASXL1 in terminal granulocyte maturation. Terminal maturation is accompanied by down regulation of Myc expression and cell cycle exit. ASXL1 deletion leads to hyperactivation of Myc in granulocyte precursors and a quantitative decrease in neutrophil production. This failure of normal developmentally-associated Myc suppression is not accompanied by significant changes in the landscape of covalent histone modifications including H3K27me3. Examining the genome-wide localization of ASXL1 in myeloid progenitors revealed strong co-localization with RNA Polymerase II (RNAPII) at the promoters and spread across the gene bodies of transcriptionally active genes. ASXL1 deletion results in a decrease in RNAPII promoter-proximal pausing in granulocyte progenitors, indicative of a global increase in productive transcription, consistent with the known role of ASXL1 as a mediator of RNAPII pause release. These results suggest that ASXL1 inhibits productive transcription in granulocyte progenitors, identifying a new role for this epigenetic regulator and highlighting a novel possible oncogenic mechanism for ASXL1 mutations in myeloid malignancies.
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Project description:De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome, a disease with severe developmental defects and early childhood fatality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models,we found that Asxl1 global loss or conditional deletion in osteoblasts and their progenitors in mice leads to significant bone loss and markedly decreased numbers of marrow mesenchymal stem/progenitor cells (MSPCs) compared with wild-type (WT) littermates. Asxl1-/- MSPCs displayed impaired self-renewal and skewed differentiation-away from osteoblasts and favoring adipocytes. RNA-seq analysis reveals the altered expression of genes involved in cell proliferation, skeletal development and morphogenesis. Furthermore, gene set enrichment analysis showed a decreased gene expression of stem cell self-renewal signature,suggesting the role of Asxl1 in regulating the stemness of MSPCs. Importantly, introducing Asxl1 normalized NANOG and OCT4 expression and restored the self-renewal capacity of Asxl1-/- MSPCs. Our study unveils a pivotal role of ASXL1 in maintenance of MSPC functions and skeletal development. Examination of mRNA profiles in wild type and Asxl1-/- MSPCs by deep sequencing
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Project description:To assess the effect of mutant ASXL1 (ASXL1-MT) on gene expression and RNA splicing in hematopoietic cells, we performed RNA-seq using HSPCs (bone marrow lineage-, c-Kit+ cells) derived from control or ASXL1-MT-KI mice.
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Project description:De novo ASXL1 mutations are found in patients with Bohring-Opitz syndrome (BOS), a disease with severe developmental defects and early childhood fatality. The underlying pathologic mechanisms remain largely unknown. Using Asxl1-targeted murine models, we found that Asxl1 global loss or conditional deletion in osteoblasts and their progenitors in mice leads to significant bone loss and markedly decreased numbers of marrow mesenchymal stem/progenitor cells (MSPCs) compared with wild-type (WT) littermates. Asxl1 null MSPCs display impaired self-renewal and skewed differentiation from osteoblasts towards adipocytes. ChIP-seq data identified that ASXL1 and H3K4me3 co-occupy the promoter regions of genes critical for MSPC self-renewal. Loss of Asxl1 diminished the genome enrichment of H3K4me3. Combined analysis of RNA-seq and ChIP-seq data revealed that Asxl1 loss in MSPCs altered the expression of ASXL1/H3K4me3 target genes controlling self-renewal/lineage commitment. Our study unveil a pivotal role of ASXL1 in H3K4me3-associated bone homeostasis
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Project description:Asxl1 is one of the most commonly mutated genes in malignancies including myelodysplastic syndromes (MDS) and Acute Myeloid Leukemia (AML). We generated a mouse model that harbors the most common mutation on ASXL1 gene detected in MDS patients: c.1934dupG, p.G646WfsX12 at the endogenous murine Asxl1 locus: the G643WfsX12 mutant, from here on referred as Asxl1G643W. Mutations on Asxl1 co-occur with mutations on CEBPA in AML patients, therefore, in order to understand how Asxl1 and Cebpa co-operate, we set up to cross our Cebpa-p30 mutant mouse model with our newly generated Asxl1 G643Wfs12 mutant. In this study we provided mechanistic information about the cooperation between these two factors. Furthermore, our mouse model proved able to recapitulate the chemotherapy response of human patients with Asxl1 mutations, thus representing a potent tool for future preclinical studies focusing on Asxl1 mutant AML.
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