Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA396050 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5876670.fastq.gz | Fastqsanger.gz | |||
| SRR5876680.fastq.gz | Fastqsanger.gz | |||
| SRR5876661_1.fastq.gz | Fastqsanger.gz | |||
| SRR5876661_2.fastq.gz | Fastqsanger.gz | |||
| SRR5876671.fastq.gz | Fastqsanger.gz |
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Project description:Chromatin remodeling by the SWI/SNF complex is essential for hematopoietic lineage commitment and differentiation. While core subunits ARID1A and ARID1B are frequently mutated in B cell malignancies, their specific roles in B cell development and transformation remain poorly understood. Here, we investigated the function of these SWI/SNF components using conditional knockout mice with CD19-Cre–mediated deletion, initiated at the pro-B cell stage. Loss of either Arid1a or Arid1b led to a partial block in B cell differentiation in the bone marrow and impaired germinal center formation following antigen exposure. Double deletion of Arid1a and Arid1b resulted in a more severe phenotype, with marked reduction in peripheral B cells, shortened overall survival, and development of an aggressive leukemia. Surprisingly, the malignancy was of myeloid origin, arising from a small subset of CD19-expressing multipotent progenitors (MPPs). These Arid1a/Arid1b-deficient MPPs exhibited abnormal expansion, defective differentiation in methylcellulose assays, and transcriptional dysregulation of key self-renewal programs driven by CBFA2T3 (ETO2) and Fli1. In established B cell lymphoma cells in vitro, loss of ARID1A and ARID1B together mildly affected cell growth, while loss of ARID1A increased sensitivity to pharmacological EZH2 inhibition. Collectively, our findings reveal stage-specific and compensatory roles for ARID1A and ARID1B in B cell development, uncover a previously unrecognized mechanism by which SWI/SNF loss in early progenitors can drive transformation towards myeloid leukemia, and identified possible therapeutic vulnerabilities in patients with ARID1A mutations.
2025-09-15 | GSE307527 | GEO
Project description:ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation. Changes in accessibility are predictive of changes in expression and correlate with loss of H3K4me and H3K27ac marks, nucleosome spacing, and transcription factor binding, particularly at growth pathway genes including MET. We find that ARID1B knockdown in ARID1A mutant ovarian cancer cells causes similar loss of enhancer architecture, suggesting that this is a conserved function underlying the synthetic lethality between ARID1A and ARID1B.
2017-09-29 | GSE101966 | GEO
Project description:ARID1A, a subunit of the SWI/SNF chromatin remodeling complex, is frequently mutated in cancer. Deficiency in its homolog ARID1B is synthetically lethal with ARID1A mutation. However, the functional relationship between these homologs has not been explored. Here we use ATAC-seq, genome-wide histone modification mapping, and expression analysis to examine colorectal cancer cells lacking one or both ARID proteins. We find that ARID1A has a dominant role in maintaining chromatin accessibility at enhancers, while the contribution of ARID1B is evident only in the context of ARID1A mutation. Changes in accessibility are predictive of changes in expression and correlate with loss of H3K4me and H3K27ac marks, nucleosome spacing, and transcription factor binding, particularly at growth pathway genes including MET. We find that ARID1B knockdown in ARID1A mutant ovarian cancer cells causes similar loss of enhancer architecture, suggesting that this is a conserved function underlying the synthetic lethality between ARID1A and ARID1B.
2017-09-29 | GSE101974 | GEO
Project description:The BAF complex modulates chromatin accessibility. Specific BAF configurations have functional consequences, and subunit switches are essential for cell differentiation. ARID1B and its paralog ARID1A encode for mutually exclusive BAF subunits. De novo ARID1B haploinsufficient mutations cause a neurodevelopmental disorder spectrum, including Coffin-Siris syndrome, which is characterized by neurological and craniofacial features. Here, we reprogrammed ARID1B+/- Coffin-Siris patient-derived skin fibroblasts into iPSCs, and modeled cranial neural crest cell (CNCC) formation. We discovered that ARID1B is active only during the first stage of this process, coinciding with neuroectoderm specification, where it is part of a lineage-specific BAF configuration (ARID1B-BAF), including SMARCA4, and nine additional subunits. ARID1B-BAF acts as a gate-keeper, ensuring exit from pluripotency and lineage commitment, by attenuating NANOG, SOX2 and the thousands of enhancers directly regulated by these two pluripotency factors at the iPSC stage. In iPSCs, these enhancers are maintained active by an ARID1A-containing BAF. At the onset of differentiation, cells transition from ARID1A-BAF to ARID1B-BAF, eliciting attenuation of the NANOG/SOX2 networks, and triggering pluripotency exit. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at pluripotency enhancers throughout all stages of CNCC formation. This leads to a persistent and aberrant SOX2 and NANOG activity, which impairs CNCC formation. In fact, despite showing the typical neural crest signature (TFAP2A+, SOX9+), the ARID1B-haploinsufficient CNCCs are also NANOG-positive, in stark contrast with the ARID1B-wt CNCCs, which are NANOG-negative. These findings suggest a connection between ARID1B mutations, neuroectoderm formation, and a pathogenic mechanism for Coffin-Siris syndrome.
2021-10-12 | PXD028557 | Pride
Project description:ARID1A and ARID1B loss in HCT116 and TOV21G cells
| PRJNA396048 | ENA
Project description:De-novo ARID1B haploinsufficient mutations cause many developmental disorders characterized by neurological and craniofacial phenotypes, including Coffin-Siris Syndrome. ARID1B and its paralog ARID1A encode for mutually exclusive subunits of the BAF chromatin remodeler, yet their role in cell-fate determination is poorly understood. We discovered a novel neural crest configuration of the BAF complex (ARID1B-BAF), which includes ARID1B, SMARCA4, and eight additional subunits. The ARID1B-BAF regulates lineage commitment upon differentiation cues through attenuation of pluripotency enhancers of the SOX2 network. Consistently, the ARID1B-BAF interacts with SALL4, which is known to have repressing abilities during lineage commitment. In iPSCs, pluripotency enhancers are maintained in active state by cooperation between the pioneer activity of SOX2 and the ARID1A-containing BAF. At the onset of differentiation, ARID1B-BAF replaces ARID1A-BAF at these enhancers, eliciting chromatin repression and coordinating the exit from pluripotency. Coffin-Siris patient cells fail to perform the ARID1A/ARID1B switch, and maintain ARID1A-BAF at the pluripotency enhancers throughout CNCC differentiation. This correlates with aberrant SOX2 binding at the pluripotency enhancers, and failure to reposition SOX2 at the developmental enhancers. SOX2 dysregulation promotes upregulation of the NANOG regulatory network, impairing CNCC differentiation. Intriguingly, the patient with the most extreme molecular phenotype is also affected by a more severe version of the syndrome. These findings have significant biomedical implications, since they suggest a direct connection between ARID1B mutations and developmental disorders.
2021-09-22 | GSE169654 | GEO
Project description:Gene expression profiling of immortalized human mesenchymal stem cells with hTERT/E6/E7 transfected MSCs. hTERT may change gene expression in MSCs. Goal was to determine the gene expressions of immortalized MSCs.
2010-09-25 | GSE24338 | GEO
Project description:Kynureninase is a member of a large family of catalytically diverse but structurally homologous pyridoxal 5'-phosphate (PLP) dependent enzymes known as the aspartate aminotransferase superfamily or alpha-family. The Homo sapiens and other eukaryotic constitutive kynureninases preferentially catalyze the hydrolytic cleavage of 3-hydroxy-l-kynurenine to produce 3-hydroxyanthranilate and l-alanine, while l-kynurenine is the substrate of many prokaryotic inducible kynureninases. The human enzyme was cloned with an N-terminal hexahistidine tag, expressed, and purified from a bacterial expression system using Ni metal ion affinity chromatography. Kinetic characterization of the recombinant enzyme reveals classic Michaelis-Menten behavior, with a Km of 28.3 +/- 1.9 microM and a specific activity of 1.75 micromol min-1 mg-1 for 3-hydroxy-dl-kynurenine. Crystals of recombinant kynureninase that diffracted to 2.0 A were obtained, and the atomic structure of the PLP-bound holoenzyme was determined by molecular replacement using the Pseudomonas fluorescens kynureninase structure (PDB entry 1qz9) as the phasing model. A structural superposition with the P. fluorescens kynureninase revealed that these two structures resemble the "open" and "closed" conformations of aspartate aminotransferase. The comparison illustrates the dynamic nature of these proteins' small domains and reveals a role for Arg-434 similar to its role in other AAT alpha-family members. Docking of 3-hydroxy-l-kynurenine into the human kynureninase active site suggests that Asn-333 and His-102 are involved in substrate binding and molecular discrimination between inducible and constitutive kynureninase substrates.
| S-EPMC2531291 | biostudies-literature
Project description:Recent unbiased exome and whole-genome sequencing studies have identified ARID1B (originally BAF250b) as the most frequently mutated gene in human de novo neurodevelopmental disorders and a high confidence autism gene. ARID1B is a subunit of the multimeric SWI/SNF or Brg/Brahma-Associated Factor (BAF) ATP-dependent chromatin remodeling complex. Studies of Arid1b+/- mice as well as other BAF subunit mutants have found defects in neural progenitor proliferation and activity-dependent neuronal dendritogenesis; however, to date, the molecular impact of ARID1B mutations on the human neural lineage has not been investigated. Remarkably, ARID1B is required for expression of HOX genes, including anterior HOX genes necessary for brain development. Despite the high homology with ARID1A and the fact that ARID1A is expressed at about 3-fold higher levels, it is unable to compensate for heterozygous loss of ARID1B. These changes in gene expression were paralleled by dosage-sensitive altered deposition of histone H3 lysine-27 trimethylation (H3K27me3) and histone H2A lysine-119 ubiquitination (H2AK119ub) indicating that an evolutionarily conserved pathway of HOX gene regulation underlies the neurodevelopmental defects accompanying ARID1B haploinsufficiency. Using FIRE-Cas9, we show that the unmutated ARID1B allele can be activated to near normal and potentially therapeutic levels.
2021-11-20 | GSE188883 | GEO