Expression data from Arid4b knockdown cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE35731 | GEO | 2012/04/24
SECONDARY ACCESSION(S): PRJNA152139
REPOSITORIES: GEO
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Project description:High Arid4b promotes mammary tumor growth and metastasis in mouse model systems, and is associated with poor metastasis-free survival in human breast cancer patients. Through shRNA-mediated knockdown, we demonstrated that loss of Arid4b significantly inhibits the ability of mouse breast cancer cells to metastasize to the lungs. We performed microarray expression and subsequent network analysis to identify genes diferentially regulated as a consequence of Arid4b knockdown. The highly metastatic mouse breast cancer cell line 6DT1 was transduced with lentiviral shRNAs targeting Arid4b (RMM4534-NM_194262, Open Biosystems) or scrambled control in the same pLKO.1 vector backbone. Stably transduced cells were selected with puromycin, then total RNA was isolated from pooled clones.
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Project description:Phosphatase and tensin homologue (PTEN) is the most frequently mutated tumor suppressor gene in human prostate cancer. Synthetic essentiality is defined as cancer that harbors a specific tumor suppressor deficiency is dependent on synthetic-essential genes for the malignant phenotypes. Recently, targeting such synthetic-essential genes has become an attractive treatment approach for cancers that acquire loss-of-function mutations in tumor suppressor genes. Here, we show that AT-rich interaction domain 4B (ARID4B) functions as a synthetic-essential gene in prostate tumorigenesis driven by PTEN deficiency. This functional interaction between ARID4B and PTEN is recapitulated in the mouse model carrying prostate-specific deletions of Pten and Arid4b in which ablation of ARID4B attenuated prostate cancer progression elicited by loss of PTEN. Although the tumor suppressor function of PTEN is most attributed to its lipid phosphatase activity that counters the PI3K action in cytoplasm, we identified the PTEN-ARID4B-PI3K axis in which nuclear PTEN inhibits expression of ARID4B, while ARID4B serves as a transcriptional activator of the PI3K subunits PIK3CA and PIK3R2 to trigger the PI3K/AKT pathway. Our study further demonstrated that the reciprocal binding of ARID4B and histone H1 to the PIK3CA and PIK3R2 promoters modulates chromatin condensation, indicating a mechanism by which ARID4B activates these promoters. Finally, a three-gene signature consisting of PTEN, ARID4B, and PI3K substantially improves the predictive power for tumor recurrence in human prostate cancer patients, underscoring the clinical significance of this newly identified PTEN-ARID4B-PI3K axis. These findings reveal a novel synthetic-essential relationship between ARID4B and PTEN, thus exposing a previously unidentified cancer-specific vulnerability, and supporting ARID4B as a potential therapeutic target for prostate cancer patients with PTEN mutations.
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Project description:Phosphatase and tensin homologue (PTEN) is the most frequently mutated tumor suppressor gene in human prostate cancer. Synthetic essentiality is defined as cancer that harbors a specific tumor suppressor deficiency is dependent on synthetic-essential genes for the malignant phenotypes. Recently, targeting such synthetic-essential genes has become an attractive treatment approach for cancers that acquire loss-of-function mutations in tumor suppressor genes. Here, we show that AT-rich interaction domain 4B (ARID4B) functions as a synthetic-essential gene in prostate tumorigenesis driven by PTEN deficiency. This functional interaction between ARID4B and PTEN is recapitulated in the mouse model carrying prostate-specific deletions of Pten and Arid4b in which ablation of ARID4B attenuated prostate cancer progression elicited by loss of PTEN. Although the tumor suppressor function of PTEN is most attributed to its lipid phosphatase activity that counters the PI3K action in cytoplasm, we identified the PTEN-ARID4B-PI3K axis in which nuclear PTEN inhibits expression of ARID4B, while ARID4B serves as a transcriptional activator of the PI3K subunits PIK3CA and PIK3R2 to trigger the PI3K/AKT pathway. Our study further demonstrated that the reciprocal binding of ARID4B and histone H1 to the PIK3CA and PIK3R2 promoters modulates chromatin condensation, indicating a mechanism by which ARID4B activates these promoters. Finally, a three-gene signature consisting of PTEN, ARID4B, and PI3K substantially improves the predictive power for tumor recurrence in human prostate cancer patients, underscoring the clinical significance of this newly identified PTEN-ARID4B-PI3K axis. These findings reveal a novel synthetic-essential relationship between ARID4B and PTEN, thus exposing a previously unidentified cancer-specific vulnerability, and supporting ARID4B as a potential therapeutic target for prostate cancer patients with PTEN mutations.
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Project description:Hematopoiesis is maintained by a highly regulated and hierarchical system, whereas aberrant control of hematopoiesis is the underlying cause of severe hematological diseases. Here, we demonstrate the indispensable role of ARID4B in fetal hematopoiesis that recruits Ezh2 to transcriptionally downregulate the expression of KIT during erythroid cell differentiation. Functional analyses reveal that the aberration of Arid4b inhibits fetal hematopoiesis at the multipotent progenitors (MPPs) stage, which reactivates the KIT-Src-family kinase (Src) pathway and leads to pre-mature erythroblast proliferation. The differentiation defect caused by ARID4B aberration could be counteracted by the Src inhibitor PP2 or by KIT knockdown. In summary, we identify ARID4B as a master regulator in the KIT-Src pathway, thus providing a fundamental insight in hematopoiesis and stem cell regulation.
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Project description:Hematopoiesis is maintained by a highly regulated and hierarchical system, whereas aberrant control of hematopoiesis is the underlying cause of severe hematological diseases. Here, we demonstrate the indispensable role of ARID4B in fetal hematopoiesis that recruits Ezh2 to transcriptionally downregulate the expression of KIT during erythroid cell differentiation. Functional analyses reveal that the aberration of Arid4b inhibits fetal hematopoiesis at the multipotent progenitors (MPPs) stage, which reactivates the KIT-Src-family kinase (Src) pathway and leads to pre-mature erythroblast proliferation. The differentiation defect caused by ARID4B aberration could be counteracted by the Src inhibitor PP2 or by KIT knockdown. In summary, we identify ARID4B as a master regulator in the KIT-Src pathway, thus providing a fundamental insight in hematopoiesis and stem cell regulation.
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Project description:The role of ARID4B in breast cancer development has not been completely elucidated. The aim of this study was to investigate the effect of loss of function mutations generated using the CRISPR/Cas9 system in human breast cancer cells. For this, we characterized the proliferation, viability, and migration rates of different clones with insertions and deletions compared to wild-type cells. We report the transcriptomic profile of mutated MCF-7 clones and negative control.
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Project description:Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies focused on epigenetic factors that affect ESC self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been studied extensively. We have set out to identify chromatin related factors critical for differentiation towards mesodermal and endodermal lineages. Our results reveal a critical role for chromatin protein, Arid4b. Arid4b deficient mESCs are similar to wild-type mESCs in the expression of pluripotency factors and their self-renewal. However, we found that Arid4b loss results in defects in upregulation of meso/endodermal gene expression program. Arid4b is in the Sin3a complex along with Hdac1 and Hdac2. We identified a physical and functional interaction of Arid4b with Hdac1 rather than Hdac2. Arid4b deficiency leads to changes in the overall chromatin environment. Most notably, a subset of the genomic loci was found to gain H3K27Ac whereas several of the key developmental genes instead have increased H3K27me3 levels. Accordingly, the super-enhancers associated with meso/endoderm commitment were selectively reduced in arid4b∆ cells.
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Project description:Distinct cell types emerge from embryonic stem cells through a precise and coordinated execution of gene expression programs during lineage commitment. This is established by the action of lineage specific transcription factors along with chromatin complexes. Numerous studies focused on epigenetic factors that affect ESC self-renewal and pluripotency. However, the contribution of chromatin to lineage decisions at the exit from pluripotency has not been studied extensively. We have set out to identify chromatin related factors critical for differentiation towards mesodermal and endodermal lineages. Our results reveal a critical role for chromatin protein, Arid4b. Arid4b deficient mESCs are similar to wild-type mESCs in the expression of pluripotency factors and their self-renewal. However, we found that Arid4b loss results in defects in upregulation of meso/endodermal gene expression program. Arid4b is in the Sin3a complex along with Hdac1 and Hdac2. We identified a physical and functional interaction of Arid4b with Hdac1 rather than Hdac2. Arid4b deficiency leads to changes in the overall chromatin environment. Most notably, a subset of the genomic loci was found to gain H3K27Ac whereas several of the key developmental genes instead have increased H3K27me3 levels. Accordingly, the super-enhancers associated with meso/endoderm commitment were selectively reduced in arid4b∆ cells.
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