BRD9 is essential for ribosome biogenesis and survival of multiple myeloma cells.
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA810599 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18148044_1.fastq.gz | Fastqsanger.gz | |||
| SRR18148044_2.fastq.gz | Fastqsanger.gz | |||
| SRR18148045_1.fastq.gz | Fastqsanger.gz | |||
| SRR18148045_2.fastq.gz | Fastqsanger.gz | |||
| SRR18148046_1.fastq.gz | Fastqsanger.gz |
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Project description:BRD9 is a defining component of the non-canonical SWI/SNF complex, regulating gene expression by controlling chromatin dynamics. We here identified high BRD9 expression as a poor prognostic factor in multiple myeloma (MM), which is positively correlated with activation of ribosome biogenesis. Genetic and pharmacological depletion of BRD9 downregulates expression of ribosome biogenesis genes and disrupts protein synthesis maintenance machinery, thereby inhibiting MM cell growth in both in vitro and in vivo preclinical models. Importantly, BRD9 interacts with BRD4 and MYC to form a transcription initiation complex that promotes transcription of ribosomal biogenesis genes. These results identify and validate BRD9 as a novel therapeutic target in MM which regulates ribosome biogenesis gene transcription, and provide the framework for clinical evaluation of BRD9 degraders to improve patient outcome in MM. This SuperSeries is composed of the SubSeries listed below.
2023-02-08 | GSE197486 | GEO
Project description:BRD9 is a defining component of the non-canonical SWI/SNF complex, regulating gene expression by controlling chromatin dynamics. We here identified high BRD9 expression as a poor prognostic factor in multiple myeloma (MM), which is positively correlated with activation of ribosome biogenesis. Genetic and pharmacological depletion of BRD9 downregulates expression of ribosome biogenesis genes and disrupts protein synthesis maintenance machinery, thereby inhibiting MM cell growth in both in vitro and in vivo preclinical models. Importantly, BRD9 interacts with BRD4 and MYC to form a transcription initiation complex that promotes transcription of ribosomal biogenesis genes. These results identify and validate BRD9 as a novel therapeutic target in MM which regulates ribosome biogenesis gene transcription, and provide the framework for clinical evaluation of BRD9 degraders to improve patient outcome in MM. This SuperSeries is composed of the SubSeries listed below.
2023-02-08 | GSE197487 | GEO
Project description:PurposeBRD9 is a defining component of the noncanonical SWI/SNF complex, which regulates gene expression by controlling chromatin dynamics. Although recent studies have found an oncogenic role for BRD9 in multiple cancer types including multiple myeloma, its clinical significance and oncogenic mechanism have not yet been elucidated. Here, we sought to identify the clinical and biological impact of BRD9 in multiple myeloma, which may contribute to the development of novel therapeutic strategies.Experimental designWe performed integrated analyses of BRD9 in vitro and in vivo using multiple myeloma cell lines and primary multiple myeloma cells in established preclinical models, which identified the molecular functions of BRD9 contributing to multiple myeloma cell survival.ResultsWe found that high BRD9 expression was a poor prognostic factor in multiple myeloma. Depleting BRD9 by genetic (shRNA) and pharmacologic (dBRD9-A; proteolysis-targeting chimera; BRD9 degrader) approaches downregulated ribosome biogenesis genes, decreased the expression of the master regulator MYC, and disrupted the protein-synthesis maintenance machinery, thereby inhibiting multiple myeloma cell growth in vitro and in vivo in preclinical models. Importantly, we identified that the expression of ribosome biogenesis genes was associated with the disease progression and prognosis of patients with multiple myeloma. Our results suggest that BRD9 promotes gene expression by predominantly occupying the promoter regions of ribosome biogenesis genes and cooperating with BRD4 to enhance the transcriptional function of MYC.ConclusionsOur study identifies and validates BRD9 as a novel therapeutic target in preclinical models of multiple myeloma, which provides the framework for the clinical evaluation of BRD9 degraders to improve patient outcome.
| S-EPMC10150249 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-02-08 | GSE197492 | GEO
Project description:Post-transcriptional regulation of Ribosome Biogenesis
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Project description:Leukemia is characterized by genetic and epigenetic mutations resulting in selection of cancer stem cells, which are unable to differentiate. While genetic alterations are difficult to target, the epigenome is intrinsically dynamic and readily offers new therapeutic strategies. Thus, identifying cancer-specific context-dependent targets and unraveling their biological function may open up new therapeutic perspectives. Here, we identify bromodomain-containing protein 9 (BRD9) as a critical target required in acute myeloid leukemia (AML). We show that BRD9 is overexpressed in AML cells including ex vivo primary blasts compared to CD34+. By targeting BRD9 expression in AML, we observed an alteration in proliferation and survival, ultimately resulting in the induction of apoptosis. Intriguingly, genome-wide profiling revealed that BRD9 binds enhancer regions in a cell type-specific manner, regulating cell type-related processes. We unveil a novel BRD9-sustained STAT5 pathway activation via regulation of SOC3 expression levels. Our findings identify a previously undescribed BRD9-STAT5 axis as critical for leukemia maintenance, suggesting BRD9 as a potential therapeutic target.
2019-11-11 | PXD013245 | Pride
Project description:The budding yeast E3 SUMO ligase Mms21, a component of the Smc5-6 complex, regulates sister chromatid cohesion, DNA replication, and DNA repair. We identify a role for Mms21 in ribosome biogenesis. The mms21RINGD mutant exhibits reduced rRNA production, nuclear accumulation of 60S and 40S ribosomal proteins, and elevated Gcn4 translation. Genes involved in ribosome biogenesis and translation are down-regulated in the mms21RINGD mutant. Examining gene expression profile of mms21RINGD mutant compared to wild-type by RNA Seq using Ilumina sequencing
2015-06-13 | E-GEOD-69826 | biostudies-arrayexpress
Project description:The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.
2020-09-14 | GSE137951 | GEO
Project description:In all domains of life, the rate of protein synthesis is directly linked to the rates of cell growth and proliferation. Consequently, highly proliferative cancer cells are especially sensitive to perturbations in ribosome biogenesis. While ribosome synthesis and cancer have a well-established relationship, only recently has ribosome biogenesis drawn interest as a cancer therapeutic target. Here, we have exploited the relationship between ribosome biogenesis and cancer cell proliferation by using a potent ribosome biogenesis inhibitor: RBI2 (Ribosome Biogenesis Inhibitor 2) to perturb cancer cell growth and viability. We demonstrate that RBI2 significantly decreases cell viability in malignant melanoma cells and breast cancer cell lines. Treatment with RBI2 dramatically and rapidly decreases ribosomal RNA (rRNA) synthesis, without affecting the occupancy of RNA polymerase I (Pol I) on the ribosomal DNA template. Next-generation RNA sequencing (RNA-seq) reveals that RBI2 and previously described ribosome biogenesis inhibitor CX-5461 induce distinct changes in the transcriptome. Investigation of the content of the pre-rRNAs through RT-qPCR reveals an increase in polyadenylation of cellular rRNA after treatment with RBI2, a known pathway by which rRNA degradation occurs. Northern blotting revealed that RBI2 does not appear to impair or alter rRNA processing. Collectively, these data suggest that RBI2 inhibits rRNA synthesis distinctly from other previously described ribosome biogenesis inhibitors, potentially through a novel pathway that upregulates turnover of premature rRNAs.
2021-11-08 | GSE188262 | GEO
Project description:The role of ribosome biogenesis in erythroid development is supported by the recognition of erythroid defects in ribosomopathies in both Diamond-Blackfan anemia and 5q- syndrome. Whether ribosome biogenesis exerts a regulatory function on normal erythroid development is still unknown. In the present study, a detailed characterization of ribosome biogenesis dynamics during human and murine erythropoiesis shows that ribosome biogenesis is abruptly interrupted by the drop of rDNA transcription and the collapse of ribosomal protein neo-synthesis. Its premature arrest by RNA polI inhibitor, CX-5461 targets the proliferation of immature erythroblasts. We also show that p53 is activated spontaneously or in response to CX-5461 concomitantly to ribosome biogenesis arrest, and drives a transcriptional program in which genes involved in cell cycle arrest, negative regulation of apoptosis and DNA damage response were upregulated. RNA polI transcriptional stress results in nucleolar disruption and activation of ATR-CHK1-p53 pathway. Our results imply that the timing of ribosome biogenesis extinction and p53 activation are crucial for erythroid development. In ribosomopathies in which ribosome availability is altered by unbalanced production of ribosomal proteins, the threshold of ribosome biogenesis down-regulation could be prematurely reached and together with pathological p53 activation prevents a normal expansion of erythroid progenitors.
2020-09-14 | GSE157208 | GEO