Pbrm1 regulates interferon signaling in mouse AML [ChIP-seq HAP1]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA869701 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR21059237_1.fastq.gz | Fastqsanger.gz | |||
| SRR21059237_2.fastq.gz | Fastqsanger.gz | |||
| SRR21059238_1.fastq.gz | Fastqsanger.gz | |||
| SRR21059238_2.fastq.gz | Fastqsanger.gz | |||
| SRR21059239_1.fastq.gz | Fastqsanger.gz |
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Project description:Pbrm1 regulates interferon signaling in mouse AML [RNA-seq HAP1]
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Project description:CRISPR/Cas9 screening approaches are powerful tools to identify in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which sequential acquisition of somatic mutations generates clonal diversity. With time, additional cooperating mutations may drive disease progression. Using an in vivo pooled genetic mutagenesis screen of epigenetic factors in primary murine HSPCs, we sought to uncover unrecognized genes that contribute to leukemia progression. We first modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs followed by transplantation. We then performed pooled mutagenesis of genes encoding epigenetic factors and identified Pbrm1/Baf180, a subunit of polybromo (PBAF) SWI/SNF chromatin remodeling complex, as a negative driver of disease progression. We found that Pbrm1 loss promoted leukemogenesis with significantly shortened latency. Pbrm1-deficient AML cells were less immunogenic, and characterized by attenuated interferon signaling and reduced MHC II expression. We explored potential relevance to human leukemia by assessing the involvement of Pbrm1 in control of interferon pathway components and found that Pbrm1 binds at promoters of a subset of these genes, and most notably at IRF1, which in turn regulates in MHC II expression. Our findings revealed a novel role of Pbrm1 in leukemia progression. More generally, CRISPR/Cas9 screening, coupled with phenotypic readouts in vivo, has revealed a pathway by which transcriptional control of interferon signaling influences leukemia cell interactions with the immune system.
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Project description:CRISPR/Cas9 screening approaches are powerful tools to identify in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which sequential acquisition of somatic mutations generates clonal diversity. With time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We first modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs followed by transplantation. We then performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and identified Pbrm1/Baf180, a subunit of polybromo BRG1/BRM-associated factor (PBAF) SWI/SNF chromatin remodeling complex, as a negative driver of disease progression. We found that Pbrm1 loss promoted leukemogenesis with significantly shortened latency. Pbrm1-deficient leukemia cells were less immunogenic, and characterized by attenuated interferon signaling and reduced MHC II expression. We explored potential relevance to human leukemia by assessing the involvement of PBRM1 in control of interferon pathway components and found that PBRM1 binds at promoters of a subset of these genes, and most notably at IRF1, which in turn regulates MHC II expression. Our findings revealed a novel role of Pbrm1 in leukemia progression. More generally, CRISPR/Cas9 screening, coupled with phenotypic readouts in vivo, has identified a pathway by which transcriptional control of interferon signaling influences leukemia cell interactions with the immune system.
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Project description:Pbrm1 regulates interferon signaling in mouse AML
| PRJNA869695 | ENA
Project description:CRISPR/Cas9 screening approaches are powerful tools to identify in vivo cancer dependencies. Hematopoietic malignancies are genetically complex disorders in which sequential acquisition of somatic mutations generates clonal diversity. With time, additional cooperating mutations may drive disease progression. Using an in vivo pooled gene editing screen of epigenetic factors in primary murine hematopoietic stem and progenitor cells (HSPCs), we sought to uncover unrecognized genes that contribute to leukemia progression. We first modeled myeloid leukemia in mice by functionally abrogating both Tet2 and Tet3 in HSPCs followed by transplantation. We then performed pooled CRISPR/Cas9 editing of genes encoding epigenetic factors and identified Pbrm1/Baf180, a subunit of polybromo BRG1/BRM-associated factor (PBAF) SWI/SNF chromatin remodeling complex, as a negative driver of disease progression. We found that Pbrm1 loss promoted leukemogenesis with significantly shortened latency. Pbrm1-deficient leukemia cells were less immunogenic, and characterized by attenuated interferon signaling and reduced MHC II expression. We explored potential relevance to human leukemia by assessing the involvement of PBRM1 in control of interferon pathway components and found that PBRM1 binds at promoters of a subset of these genes, and most notably at IRF1, which in turn regulates MHC II expression. Our findings revealed a novel role of Pbrm1 in leukemia progression. More generally, CRISPR/Cas9 screening, coupled with phenotypic readouts in vivo, has identified a pathway by which transcriptional control of interferon signaling influences leukemia cell interactions with the immune system.
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Project description:Pbrm1 regulates interferon signaling in mouse AML [RNA-seq Mouse]
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Project description:We performed a genome-scale screen for suppressors of interferon stimulated gene (ISG) expression in human haploid cells (HAP1). Ubiquitin specific peptidase 14 (USP14) was a significant hit. In order to validate USP14 as a regulator of ISG expression, we created knockouts of USP14 in HAP1 cells using CRISPR-Cas9 and performed RNA-seq on coding RNA from USP14 KO and WT cells. This data was used to determine if ISGs were upregulated in USP14 KO HAP1 cells.
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Project description:We performed a genome-scale screen for suppressors of interferon stimulated gene (ISG) expression in human haploid cells (HAP1). DEAD-box helicase 6 (DDX6) was a significant hit. In order to validate DDX6 as a regulator of ISG expression, we created knockouts of DDX6 in HAP1 cells using CRISPR-Cas9 and performed RNA-seq on coding RNA from DDX6 KO and WT cells. This data was used to determine if ISGs were upregulated in DDX6 KO HAP1 cells.
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Project description:PBRM1 was found to be mutated in a high percentage of clear cell RCCs. We performed knockdown of PBRM1 via siRNA and compared with scrambled control in three different RCC cell lines. PBRM1 siRNA and mock treated cell lines were normalized together with 'hypoxic' clear cell renal tumors and normal renal tissue samples from GSE17818.
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