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Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis

ABSTRACT: Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis

PROVIDER: PRJNA778208 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16820700_1.fastq.gz	Fastqsanger.gz
	SRR16820700_2.fastq.gz	Fastqsanger.gz
	SRR16820701_1.fastq.gz	Fastqsanger.gz
	SRR16820701_2.fastq.gz	Fastqsanger.gz
	SRR16820702_1.fastq.gz	Fastqsanger.gz

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Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis.

Project description:The Switch/Sugar Non-Fermenting (SWI/SNF) nucleosome remodeling complexes play important roles in normal development and in the development of various cancers. Core subunits of the SWI/SNF complexes have been shown to have oncogenic roles in acute myeloid leukemia. However, the roles of the unique targeting subunits, including that of Arid2 and Arid1b, in AML leukemogenesis are not well understood. Here, we used conditional knockout mouse models to elucidate their role in MLL-AF9 leukemogenesis. We uncovered that Arid2 has dual roles; enhancing leukemogenesis when deleted during leukemia initiation and yet is required during leukemia maintenance. Whereas, deleting Arid1b in either phase promotes leukemogenesis. Our integrated analyses of transcriptomics and genomic binding data showed that, globally, Arid2 and Arid1b regulate largely distinct sets of genes at different disease stages, respectively, and in comparison, to each other. Amongst the most highly dysregulated transcription factors upon their loss, Arid2 and Arid1b converged on the regulation of Etv4/Etv5, albeit in an opposing manner while also regulating distinct TFs including Gata2,Tcf4, Six4, Irf4 and Hmgn3. Our data demonstrate the differential roles of SWI/SNF subunits in AML leukemogenesis and emphasize that cellular context and disease stage are key in determining their functions during this process.

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RNA-seq study on mouse bone marrow leukemia cells isolated from secondary transplant recipients receiving conditional knockout Arid1b or Arid2 MLL-AF9 cells

Project description:We isolated whole bone marrow leukemia cells from moribund secondary transplant recipients receiving VavCre+ (control), Arid1b fl/fl VavCre+ (knockout), Arid2 fl/fl VavCre+ (knockout), MxCre+ (control), Arid1b fl/fl MxCre+ (knockout), or Arid2 fl/fl MxCre+ (knockout) primary MLL-AF9 cells. Mice receiving MxCre+ (control), Arid1b fl/fl MxCre+ (knockout), or Arid2 fl/fl MxCre+ (knockout) MLL-AF9 cells were injected with pIpC 21 days post transplant. Total RNA was isolated followed by mRNA selection. cDNA libraries were generated and NextGen Sequencing was performed.

2022-03-08 | GSE188291 | GEO

CUT&Tag of ARID1B and ARID2 in MOLM13 cells

Project description:MOLM13 cells were used to perform Cleavage Under Targets and Tagmentation (CUT&Tag) analysis to identify genomic binding sites of ARID1B and ARID2 in MLL-AF9 cells.

2022-03-08 | GSE188290 | GEO

Differential roles of BAF and PBAF subunits, Arid1b and Arid2, in MLL-AF9 leukemogenesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-03-08 | GSE188292 | GEO

CUT&Tag of ARID1B and ARID2 in MOLM13 cells

Project description:CUT&Tag of ARID1B and ARID2 in MOLM13 cells

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ARID2 promotes clear cell renal cell carcinoma in the absence of functional PBRM1 [ARID2 ChIP-seq]

Project description:Subunits of SWI/SNF chromatin remodeling complexes are frequently mutated in human malignancies. The PBAF complex is composed of multiple subunits, including the putative tumor suppressor proteins PBRM1 (BAF180) and ARID2 (BAF200) that are unique to this SWI/SNF complex. PBRM1 is mutated in various cancers, with a high mutation frequency in clear cell renal cell carcinoma (ccRCC). Here, we integrate RNA-seq, ARID2 and histone mark ChIP-seq, and ATAC-seq data to show that PBAF acts to enhance or repress gene expression depending on the genomic context. At baseline, ARID2 binds to areas of open chromatin at both active enhancers and promoters. Depletion of PBRM1 leads to attenuated and redistributed ARID2 chromatin binding that correlates significantly with gene expression changes. At enhancers, ARID2 binding loss leads to diminishment of the histone mark H3K4me1 and gene downregulation. Alternatively, at a subset of promoters, ARID2 binding loss derepresses gene expression. Interestingly, ARID2, which remains bound to other PBAF subunits after loss of PBRM1, is essential for many of the pro-tumorigenic transcriptional changes observed after loss of PBRM1, whereas other core SWI/SNF components are dispensable. Upon loss of PBRM1, ARID2 positively regulates cancer-related genes and pathways, including the cancer stem cell marker ALDH1A1 and EGF signaling, to stimulate tumor cell growth. Therefore, ARID2 is crucial for maintaining the transformed state of PBRM1-deficient ccRCC cells. In total, this study suggests a novel mechanism of transcriptional control by PBRM1, whereby its loss alters the chromatin distribution of the residual PBAF complex leading to altered transcription that promotes tumorigenesis.

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PBAF complex deficiency in melanoma mediates BAF occupancy and transcription factor dynamics (Chromatin)

Project description:ARID2 is an essential subunit of the SWI/SNF PBAF chromatin remodeler and is highly mutate in melanoma. To elucidate the role of ARID2 in melanoma biology and chromatin structure we utilized CRISPR Cas9 methodology to generate isogenic ARID2 WT and KO melanoma clonal cell lines. We further map the genomic localization of several SWI/SNF subunits, open and repressed chromatin markers, and multiple transcription factors to characterize how loss of the PBAF subcomplex alters chromatin accessibility and the melanoma transcription factor network. Finally, we characterized the transcriptional changes produced by PBAF depletion.

2022-04-05 | GSE172383 | GEO

PBAF associates with repressed chromatin to enable REST occupancy (RNA-Seq)

Project description:Multimeric SWI/SNF chromatin remodelers assemble in distinct conformations, with individual functions difficult to dissect. Importantly, mutations in specific SWI/SNF genes are enriched in distinct cancers, as the PBAF-specific component ARID2 in melanoma. Through comprehensive epigenomic profiling of SWI/SNF complexes and their associated chromatin states in melanoma and melanocytes, we found that a subset of PBAF-exclusive regions unexpectedly coexists with PRC2 and repressed chromatin. Time-resolved approaches revealed that PBAF regions are generally less sensitive to ATPase-mediated remodeling compared to BAF sites. Notably, PBAF/PRC2-bound loci are enriched for REST, a transcription factor that represses neuronal genes. In turn, absence of ARID2 and consequent PBAF loss hinders REST ability to bind and inactivate its targets, leading to upregulation of neuronal and synaptic transcripts, a gene signature also associated with ARID2 mutations in melanoma patients. In sum, we demonstrate a unique role for PBAF in generating accessibility for a silencing transcription factor at repressed chromatin.

2024-10-01 | GSE275420 | GEO

PBAF associates with repressed chromatin to enable REST occupancy (ChIP-seq)

2024-10-01 | GSE272705 | GEO

PBAF complex deficiency in melanoma mediates BAF occupancy and transcription factor dynamics (RNA-Seq)

2022-04-05 | GSE172384 | GEO