Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [RNA-Seq]
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ABSTRACT:
PROVIDER: PRJNA515685 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8451270.fastq.gz | Fastqsanger.gz | |||
| SRR8451280.fastq.gz | Fastqsanger.gz | |||
| SRR8451290.fastq.gz | Fastqsanger.gz | |||
| SRR8451300.fastq.gz | Fastqsanger.gz | |||
| SRR8451271.fastq.gz | Fastqsanger.gz |
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Project description:Mutations in the BAF chromatin remodeling complex rank among the most frequent genetic alterations in human cancers, many of which result in a loss of function of the respective subunits. Recent genomic and chemical screens have revealed synthetic lethal interactions of BAF complex subunits with each other as well as with further chromatin modifiers. Using an epigenome-focused shRNA library, we identified loss of the histone chaperone complex CAF-1 (chromatin assembly factor 1) as a synthetic lethal vulnerability of ARID1A-deficient cells that is enhanced by the androgen receptor agonist testosterone. In line with antagonistic roles of the CAF-1 and BAF complexes in nucleosome deposition and remodeling, we show that knock-down of CAF-1 subunits results in a partial reversal of the transcriptional and chromatin accessibility effects caused by loss of ARID1A. Together, our findings identify a new functional partner of the BAF chromatin remodeling complex and represent a potential novel strategy for targeting ARID1A-deficient cancers.
2022-09-01 | GSE125220 | GEO
Project description:Mutations in the BAF chromatin remodeling complex rank among the most frequent genetic alterations in human cancers, many of which result in a loss of function of the respective subunits. Recent genomic and chemical screens have revealed synthetic lethal interactions of BAF complex subunits with each other as well as with further chromatin modifiers. Using an epigenome-focused shRNA library, we identified loss of the histone chaperone complex CAF-1 (chromatin assembly factor 1) as a synthetic lethal vulnerability of ARID1A-deficient cells that is enhanced by the androgen receptor agonist testosterone. In line with antagonistic roles of the CAF-1 and BAF complexes in nucleosome deposition and remodeling, we show that knock-down of CAF-1 subunits results in a partial reversal of the transcriptional and chromatin accessibility effects caused by loss of ARID1A. Together, our findings identify a new functional partner of the BAF chromatin remodeling complex and represent a potential novel strategy for targeting ARID1A-deficient cancers.
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Project description:Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies
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Project description:Histone chaperone CAF-1 is a synthetic lethal vulnerability in the context of ARID1A deficiencies [ATAC-Seq]
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2022-09-01 | GSE125221 | GEO
Project description:ARID1A, an epigentic modifier, is often mutated in ovarian clear cell carcinoma (OCCC). In addition, EZH2 is frequently upregulated in OCCC. Inhibtion of EZH2 with an inhibitor (GSK126) selectively inhibits ARID1A-mutated cells. This study was designed to understand changes in gene expression profiles following EZH2 inhibition or ARID1A restoration. Chromatin remodelers such as ARID1A are frequently mutated in a broad array of cancers. However, targeted cancer therapy based on ARID1A mutation status has not been described. Intriguingly, ARID1A mutated cancers typically lack genomic instability, suggesting significant involvement of epigenetic mechanisms. Here we show that inhibition of the EZH2 methyltransferase acts in a synthetic lethal manner in ARID1A mutated cells. Remarkably, ARID1A mutation status correlated with response to EZH2 inhibitor. Genome-wide profiling revealed antagonistic roles of ARID1A and EZH2 in gene regulation. Further, we identified PIK3IP1 as a direct ARID1A/EZH2 target gene whose upregulation contributes to the observed synthetic lethality in the EZH2 inhibitor treated ARID1A mutated cells. Significantly, EZH2 inhibitor caused the regression of established ARID1A mutated tumors in vivo. Together, this data demonstrate a synthetic lethality between ARID1A mutation and EZH2 inhibition. They indicate that pharmacological inhibition of EZH2 represents a novel treatment strategy for ARID1A mutated cancers.
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Project description:During development, specialized cell lineages are generated through the establishment of cell type-specific transcriptional patterns and epigenetic programs. However, the precise mechanisms and regulators that maintain these specialized cell states remain largely elusive. To identify molecules that safeguard somatic cell identity, we performed two comprehensive RNAi screens targeting known and predicted chromatin regulators during transcription factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPSCs). Remarkably, subunits of the chromatin assembly factor-1 (CAF-1) complex emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation, DNA methylation and heterochromatin maintenance. Suppression of CAF-1 increased reprogramming efficiencies by several orders of magnitude and generated iPSCs two to three times faster compared to controls without affecting cell proliferation. We demonstrate that suppression of CAF-1 leads to a more accessible chromatin structure specifically at enhancer elements early during reprogramming. These changes were accompanied by increased binding of the reprogramming factor Sox2 to ESC-specific regulatory elements and earlier activation of pluripotency-associated genes. Notably, suppression of CAF-1 also enhanced iPSC formation from blood progenitors as well as the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 as an unanticipated regulator of somatic cell identity and provide a potential strategy to modulate cellular plasticity in a regenerative setting. Keywords: Genome binding/occupancy profiling by high throughput sequencing Chromatin accessibility and Sox2 bindings in CAF-1 knockdown and Renilla control during early OKSM reprogramming by high throughput sequencing
2015-12-10 | E-GEOD-72744 | biostudies-arrayexpress
Project description:During development, specialized cell lineages are generated through the establishment of cell type-specific transcriptional patterns and epigenetic programs. However, the precise mechanisms and regulators that maintain these specialized cell states remain largely elusive. To identify molecules that safeguard somatic cell identity, we performed two comprehensive RNAi screens targeting known and predicted chromatin regulators during transcription factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPSCs). Remarkably, subunits of the chromatin assembly factor-1 (CAF-1) complex emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation, DNA methylation and heterochromatin maintenance. Suppression of CAF-1 increased reprogramming efficiencies by several orders of magnitude and generated iPSCs two to three times faster compared to controls without affecting cell proliferation. We demonstrate that suppression of CAF-1 leads to a more accessible chromatin structure specifically at enhancer elements early during reprogramming. These changes were accompanied by increased binding of the reprogramming factor Sox2 to ESC-specific regulatory elements and earlier activation of pluripotency-associated genes. Notably, suppression of CAF-1 also enhanced iPSC formation from blood progenitors as well as the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 as an unanticipated regulator of somatic cell identity and provide a potential strategy to modulate cellular plasticity in a regenerative setting. Keywords: Genome binding/occupancy profiling by high throughput sequencing
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Project description:The transcriptional repression of alternative lineage genes is critical for cell fate commitment. Mechanisms by which locus-specific gene silencing is initiated and heritably maintained during cell division are not clearly understood. To study the maintenance of silent gene states, we investigated how the Cd4 gene is stably repressed in CD8+ T cells. Through CRISPR and shRNA screening, we identified the histone chaperone CAF-1 as a critical component for Cd4 repression. We found that the large subunit of CAF-1, Chaf1a, requires the N-terminal KER domain to associate with the histone deacetylases HDAC1/2 and the histone demethylase LSD1, enzymes that also participate in Cd4 silencing. When CAF-1 was lacking, Cd4 derepression was markedly enhanced in the absence of the de novo DNA methyltransferase Dnmt3a, but not the maintenance DNA methyltransferase Dnmt1. In contrast to Dnmt1, Dnmt3a deficiency did not significantly alter levels of DNA methylation at the Cd4 locus. Instead, Dnmt3a deficiency sensitized CD8+ T cells to Cd4 derepression mediated by compromised functions of histone modifying factors, including the enzymes associated with CAF-1. Thus, we propose that the heritable silencing of the Cd4 gene in CD8+ T cells exploits cooperative functions among the DNA methyltransferases, CAF-1, and histone modifying enzymes.
2019-02-13 | GSE126471 | GEO
Project description:The transcriptional repression of alternative lineage genes is critical for cell fate commitment. Mechanisms by which locus-specific gene silencing is initiated and heritably maintained during cell division are not clearly understood. To study the maintenance of silent gene states, we investigated how the Cd4 gene is stably repressed in CD8+ T cells. Through CRISPR and shRNA screening, we identified the histone chaperone CAF-1 as a critical component for Cd4 repression. We found that the large subunit of CAF-1, Chaf1a, requires the N-terminal KER domain to associate with the histone deacetylases HDAC1/2 and the histone demethylase LSD1, enzymes that also participate in Cd4 silencing. When CAF-1 was lacking, Cd4 derepression was markedly enhanced in the absence of the de novo DNA methyltransferase Dnmt3a, but not the maintenance DNA methyltransferase Dnmt1. In contrast to Dnmt1, Dnmt3a deficiency did not significantly alter levels of DNA methylation at the Cd4 locus. Instead, Dnmt3a deficiency sensitized CD8+ T cells to Cd4 derepression mediated by compromised functions of histone modifying factors, including the enzymes associated with CAF-1. Thus, we propose that the heritable silencing of the Cd4 gene in CD8+ T cells exploits cooperative functions among the DNA methyltransferases, CAF-1, and histone modifying enzymes.
2019-02-13 | GSE126470 | GEO