The tetraspanin CD53 protects stressed hematopoietic stem cells via promotion of DREAM complex-mediated quiescence
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA906926 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22461117.fastq.gz | Fastqsanger.gz | |||
| SRR22461118.fastq.gz | Fastqsanger.gz | |||
| SRR22461119.fastq.gz | Fastqsanger.gz | |||
| SRR22461120.fastq.gz | Fastqsanger.gz | |||
| SRR22461121.fastq.gz | Fastqsanger.gz |
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Project description:Hematopoietic stem cells (HSCs) cycle in response to inflammatory and other proliferative stressors; however, they must quickly return to quiescence to avoid exhaustion and maintain their functional integrity. The mechanisms that regulate this return to quiescence are not well understood. Here we show that the tetraspanin CD53 is markedly upregulated in HSCs in response to a variety of inflammatory and proliferative stimuli, and loss of CD53 is associated with prolonged cycling and reduced HSC function in the context of inflammatory stress. Mechanistically, CD53 promotes the activity of the DREAM transcriptional repressor complex, which downregulates genes associated with cycling and division. Proximity labeling and confocal fluorescent microscopy studies show that CD53 interacts with DREAM-associated proteins, specifically promoting the interaction between Rbl2/p130 and its phosphatase, PP2A, effectively stabilizing p130 protein availability for DREAM binding. Together, these data identify a novel mechanism by which stressed HSCs resist continued cycling.
2022-12-22 | GSE219050 | GEO
Project description:The hematopoietic stem cell (HSC) cycle responds to inflammatory and other proliferative stressors; however, these cells must quickly return to quiescence to avoid exhaustion and maintain their functional integrity. The mechanisms that regulate this return to quiescence are not well understood. Here, we show that tetraspanin CD53 is markedly upregulated in HSCs in response to a variety of inflammatory and proliferative stimuli and that the loss of CD53 is associated with prolonged cycling and reduced HSC function in the context of inflammatory stress. Mechanistically, CD53 promotes the activity of the dimerization partner, RB-like, E2F, and multi-vulva class B (DREAM) transcriptional repressor complex, which downregulates genes associated with cycling and division. Proximity labeling and confocal fluorescence microscopy studies showed that CD53 interacts with DREAM-associated proteins, specifically promoting the interaction between Rbl2/p130 and its phosphatase protein phosphatase 2A (PP2A), effectively stabilizing p130 protein availability for DREAM binding. Together, these data identified a novel mechanism by which stressed HSCs resist cycling.
| S-EPMC10023726 | biostudies-literature
Project description:The maintenance of quiescence is essential for tissue homeostasis. STAG2 is one of the few genes mutated in the normal urothelium of organ donors, with mutant cells undergoing positive selection 1. STAG2 is also a major tumour suppressor gene 2-4 and its inactivation is an early event in bladder carcinogenesis 1,3. However, the mechanisms through which STAG2, a cohesin component, disrupt urothelial homeostasis remain largely unknown. Here, we show that, in normal murine urothelial cells, Stag2 inactivation disrupts differentiation programs, induces a transient cell cycle entry, and primes cells for clonal expansion under stress conditions. In addition, STAG2 loss in urothelial cells expressing mutant FGFR3 - the most important bladder cancer oncogene 5 - enhances tumour formation. For the first time, we show that STAG2 co-operates with the transcriptional complex DREAM, a master regulator of quiescence 6,7, binding to common genomic sites, including genes involved in cell cycle control. STAG2 loss results in changes in the expression of DREAM targets, its composition and chromatin distribution, and in the rewiring of chromatin interactions involving DREAM binding motifs in genes critical for cell cycle entry. Our findings provide strong evidence that STAG2 loss leads to changes in 3D genome organization through a novel mechanism involving the DREAM complex, leading to the disruption of homeostatic quiescence and oncogenic sensitivity.
2026-02-03 | GSE288619 | GEO
Project description:The maintenance of quiescence is essential for tissue homeostasis. STAG2 is one of the few genes mutated in the normal urothelium of organ donors, with mutant cells undergoing positive selection 1. STAG2 is also a major tumour suppressor gene 2–4 and its inactivation is an early event in bladder carcinogenesis 1,3. However, the mechanisms through which STAG2, a cohesin component, disrupt urothelial homeostasis remain largely unknown. Here, we show that, in normal murine urothelial cells, Stag2 inactivation disrupts differentiation programs, induces a transient cell cycle entry, and primes cells for clonal expansion under stress conditions. In addition, STAG2 loss in urothelial cells expressing mutant FGFR3 —the most important bladder cancer oncogene 5— enhances tumour formation. For the first time, we show that STAG2 co-operates with the transcriptional complex DREAM, a master regulator of quiescence 6,7, binding to common genomic sites, including genes involved in cell cycle control. STAG2 loss results in changes in the expression of DREAM targets, its composition and chromatin distribution, and in the rewiring of chromatin interactions involving DREAM binding motifs in genes critical for cell cycle entry. Our findings provide strong evidence that STAG2 loss leads to changes in 3D genome organization through a novel mechanism involving the DREAM complex, leading to the disruption of homeostatic quiescence and oncogenic sensitivity.
2026-02-03 | GSE288712 | GEO
Project description:The maintenance of quiescence is essential for tissue homeostasis. STAG2 is one of the few genes mutated in the normal urothelium of organ donors, with mutant cells undergoing positive selection 1. STAG2 is also a major tumour suppressor gene 2-4 and its inactivation is an early event in bladder carcinogenesis 1,3. However, the mechanisms through which STAG2, a cohesin component, disrupt urothelial homeostasis remain largely unknown. Here, we show that, in normal murine urothelial cells, Stag2 inactivation disrupts differentiation programs, induces a transient cell cycle entry, and primes cells for clonal expansion under stress conditions. In addition, STAG2 loss in urothelial cells expressing mutant FGFR3 -the most important bladder cancer oncogene 5- enhances tumour formation. For the first time, we show that STAG2 co-operates with the transcriptional complex DREAM, a master regulator of quiescence 6,7, binding to common genomic sites, including genes involved in cell cycle control. STAG2 loss results in changes in the expression of DREAM targets, its composition and chromatin distribution, and in the rewiring of chromatin interactions involving DREAM binding motifs in genes critical for cell cycle entry. Our findings provide strong evidence that STAG2 loss leads to changes in 3D genome organization through a novel mechanism involving the DREAM complex, leading to the disruption of homeostatic quiescence and oncogenic sensitivity.
2026-02-03 | GSE288629 | GEO
Project description:The maintenance of quiescence is essential for tissue homeostasis. STAG2 is one of the few genes mutated in the normal urothelium of organ donors, with mutant cells undergoing positive selection 1. STAG2 is also a major tumour suppressor gene 2–4 and its inactivation is an early event in bladder carcinogenesis 1,3. However, the mechanisms through which STAG2, a cohesin component, disrupt urothelial homeostasis remain largely unknown. Here, we show that, in normal murine urothelial cells, Stag2 inactivation disrupts differentiation programs, induces a transient cell cycle entry, and primes cells for clonal expansion under stress conditions. In addition, STAG2 loss in urothelial cells expressing mutant FGFR3 —the most important bladder cancer oncogene 5— enhances tumour formation. For the first time, we show that STAG2 co-operates with the transcriptional complex DREAM, a master regulator of quiescence 6,7, binding to common genomic sites, including genes involved in cell cycle control. STAG2 loss results in changes in the expression of DREAM targets, its composition and chromatin distribution, and in the rewiring of chromatin interactions involving DREAM binding motifs in genes critical for cell cycle entry. Our findings provide strong evidence that STAG2 loss leads to changes in 3D genome organization through a novel mechanism involving the DREAM complex, leading to the disruption of homeostatic quiescence and oncogenic sensitivity.
2026-02-03 | GSE289429 | GEO
Project description:The maintenance of quiescence is essential for tissue homeostasis. STAG2 is one of the few genes mutated in the normal urothelium of organ donors, with mutant cells undergoing positive selection 1. STAG2 is also a major tumour suppressor gene 2–4 and its inactivation is an early event in bladder carcinogenesis 1,3. However, the mechanisms through which STAG2, a cohesin component, disrupt urothelial homeostasis remain largely unknown. Here, we show that, in normal murine urothelial cells, Stag2 inactivation disrupts differentiation programs, induces a transient cell cycle entry, and primes cells for clonal expansion under stress conditions. In addition, STAG2 loss in urothelial cells expressing mutant FGFR3 —the most important bladder cancer oncogene 5— enhances tumour formation. For the first time, we show that STAG2 co-operates with the transcriptional complex DREAM, a master regulator of quiescence 6,7, binding to common genomic sites, including genes involved in cell cycle control. STAG2 loss results in changes in the expression of DREAM targets, its composition and chromatin distribution, and in the rewiring of chromatin interactions involving DREAM binding motifs in genes critical for cell cycle entry. Our findings provide strong evidence that STAG2 loss leads to changes in 3D genome organization through a novel mechanism involving the DREAM complex, leading to the disruption of homeostatic quiescence and oncogenic sensitivity.
2026-02-03 | GSE288725 | GEO
Project description:The maintenance of quiescence is essential for tissue homeostasis. STAG2 is one of the few genes mutated in the normal urothelium of organ donors, with mutant cells undergoing positive selection 1. STAG2 is also a major tumour suppressor gene 2–4 and its inactivation is an early event in bladder carcinogenesis 1,3. However, the mechanisms through which STAG2, a cohesin component, disrupt urothelial homeostasis remain largely unknown. Here, we show that, in normal murine urothelial cells, Stag2 inactivation disrupts differentiation programs, induces a transient cell cycle entry, and primes cells for clonal expansion under stress conditions. In addition, STAG2 loss in urothelial cells expressing mutant FGFR3 —the most important bladder cancer oncogene 5— enhances tumour formation. For the first time, we show that STAG2 co-operates with the transcriptional complex DREAM, a master regulator of quiescence 6,7, binding to common genomic sites, including genes involved in cell cycle control. STAG2 loss results in changes in the expression of DREAM targets, its composition and chromatin distribution, and in the rewiring of chromatin interactions involving DREAM binding motifs in genes critical for cell cycle entry. Our findings provide strong evidence that STAG2 loss leads to changes in 3D genome organization through a novel mechanism involving the DREAM complex, leading to the disruption of homeostatic quiescence and oncogenic sensitivity.
2026-02-03 | GSE288819 | GEO
Project description:The DREAM complex represses cell-cycle gene transcription in quiescence. To investigate the role of the DREAM component Lin37, we created Lin37 knockout cells by CRISPR/Cas9-nickase. pRTS episomal vectors expressing luciferase or Lin37 were introduced in two independent knockout clones (411-27 and 632-2) to create Lin37 knockout and rescue cells. To exit the cell cycle and to enter quiescence, cells were serum starved for 60h. RNA-seq was applied to identify genes de-regulated by loss of Lin37 during quiescence.
2017-08-17 | GSE97716 | GEO
Project description:The tumor suppressor STAG2 cooperates with DREAM to maintain quiescence in the urothelium
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