Lin37 is essential for repression of cell-cycle genes in quiescence
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE97716 | GEO | 2017/08/17
SECONDARY ACCESSION(S): PRJNA382716
REPOSITORIES: GEO
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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.
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Project description:The DREAM (DP, Retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell cycle and other genes, but its mechanism of action is unclear. Here we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z. Furthermore, the function of DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses a subset of germline targets by facilitating H3K9me2 promoter marking. In humans, THAP proteins have been implicated in cell cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function, facilitating repression of distinct sets of targets.
2020-08-13 | GSE155189 | GEO
Project description:The DREAM (DP, Retinoblastoma [Rb]-like, E2F, and MuvB) complex controls cellular quiescence by repressing cell cycle and other genes, but its mechanism of action is unclear. Here we demonstrate that two C. elegans THAP domain proteins, LIN-15B and LIN-36, co-localize with DREAM and function by different mechanisms for repression of distinct sets of targets. LIN-36 represses classical cell cycle targets by promoting DREAM binding and gene body enrichment of H2A.Z. Furthermore, the function of DREAM subunit EFL-1/E2F is specific for LIN-36 targets. In contrast, LIN-15B represses a subset of germline targets by facilitating H3K9me2 promoter marking. In humans, THAP proteins have been implicated in cell cycle regulation by poorly understood mechanisms. We propose that THAP domain proteins are key mediators of Rb/DREAM function, facilitating repression of distinct sets of targets.
2020-08-13 | GSE155190 | GEO
Project description:Hair follicle stem cells(HFSCs) can transition between active and quiescent stages during normal hair cycle or would healing. Transcriptional regulation has been show to regulate the transition. Previous studies have shown that two transcription factor, Foxc1 and Nfatc1, can help maintain the stem cells in quiescent state, the deletion of either one could lead to precocious activation. Here, we collect the hair follicle stem cell at postnatal day 30 from both control mice, Nfatc1 knockout mice, Foxc1 knockout mice(downloaded) and Foxc1/Nfatc1 double knockout mice to study the transcriptional regulation network of HFSCs quiescence.
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Project description:Quiescence is an actively maintained state of the cell cycle;aberrations in which can result in severe consequencces for development and tissue homeostasis. Primary cilia are signaling centres derived from the centrosome which are associated with quiescence.Using a mouse skeletal myoblast cell culture system that can be induced to exit the cell cycle reversibly into quiescence or irreversibly into differentiation, we studied the effect of loss of ciliogenesis on quiescence.
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Project description:Background: Although quiescence—reversible cell-cycle arrest—is a key part in the life history and fate of many mammalian cell types, the mechanisms of gene regulation in quiescent cells are poorly understood. We sought to clarify the role of microRNAs as regulators of the cellular functions of quiescent human fibroblasts. Results: Using microarrays, we discovered that the expression of the majority of profiled microRNAs differed between proliferating and quiescent fibroblasts. Fibroblasts induced into quiescence by contact inhibition or serum starvation had similar microRNA profiles, indicating common changes induced by distinct quiescence signals. By analyzing the gene expression patterns of microRNA target genes with quiescence, we discovered a strong regulatory function for miR-29, which is downregulated with quiescence. Using microarrays and immunoblotting, we confirmed that miR-29 targets genes encoding collagen and other extracellular matrix proteins and that those target genes are induced in quiescence. In addition, overexpression of miR-29 resulted in more rapid cell cycle re-entry from quiescence. We also found that let-7 and miR-125 were upregulated in quiescent cells. Overexpression of either one alone resulted in slower cell cycle re-entry from quiescence, while the combination of both together slowed cell cycle re-entry even further. Conclusions: microRNAs regulate key aspects of fibroblast quiescence including the proliferative state of the cells as well as their gene expression profiles, in particular, the induction of extracellular matrix proteins in quiescent fibroblasts. microRNAs in human neonatal dermal fibroblasts in 3 cell cycle conditions (proliferating, 4 days serum starved, 7 days contact inhibited) were analyzed by one color microarray. 3 separate fibroblast cell lines from different human donors were analyzed for each condition, with two separate labeling and hybridization samples for each cell line. In total, 18 samples were hybridized to the microRNA microarray.
2012-12-05 | E-GEOD-42593 | biostudies-arrayexpress
Project description:The mammalian Retinoblastoma (RB) family including pRB, p107, and p130 represses E2F target genes through mechanisms that are not fully understood. In D. melanogaster, RB-dependent repression is mediated in part by the multisubunit protein complex Drosophila RBF, E2F, and Myb (dREAM) that contains homologs of the C. elegans synthetic multivulva class B (synMuvB) gene products. Using an integrated approach combining proteomics, genomics, and bioinformatic analyses, we identified a p130 complex termed DP, RB-like, E2F, and MuvB (DREAM) that contains mammalian homologs of synMuvB proteins LIN-9, LIN-37, LIN-52, LIN-54, and LIN-53/RBBP4. DREAM bound to more than 800 human promoters in G0 and was required for repression of E2F target genes. In S phase, MuvB proteins dissociated from p130 and formed a distinct submodule that bound MYB. This work reveals an evolutionarily conserved multisubunit protein complex that contains p130 and E2F4, but not pRB, and mediates the repression of cell cycle-dependent genes in quiescence. Experiment Overall Design: Gene expression during the cell cycle in T98G cells. Cells were serum starved for 72 hours to induce G0 and then restimuated to enter cell cycle by serum addition. BrdU and FACS was done simultaneously to confirm their cell cycle phase.
2008-06-16 | E-GEOD-8537 | biostudies-arrayexpress
Project description:Quiescence and limited dividing are critical in preserving potency of hematopoietic stem/progenitor cell (HSPCs) during lifetime, but little is known about how this process is regulated. Here, we show that the mobilized human HSPCs in peripheral blood (PB) are predominantly in a quiescent state, but rapidly exit quiescence and reduce repopulating potency in short-term culture. Through single cell RNA-seq, we identified a panel of regulators highly associated with HSC quiescence exit and cell-cycle entry. These regulators involve different biological processes such as cell-cycle, signaling pathways, metabolisms, etc. Among them, the oncogene, FOS restrains cell-cycle entry and supports repopulating potency in human HSCs through directly binding and regulating genes both for HSC quiescence and potency. Our findings uncover the regulatory program underlying quiescence exit and highlight the critical role of FOS to guard the quiescence and potency in human HSPCs.
2021-06-08 | GSE176316 | GEO
Project description:Quiescence and limited dividing are critical in preserving potency of hematopoietic stem/progenitor cell (HSPCs) during lifetime, but little is known about how this process is regulated. Here, we show that the mobilized human HSPCs in peripheral blood (PB) are predominantly in a quiescent state, but rapidly exit quiescence and reduce repopulating potency in short-term culture. Through single cell RNA-seq, we identified a panel of regulators highly associated with HSC quiescence exit and cell-cycle entry. These regulators involve different biological processes such as cell-cycle, signaling pathways, metabolisms, etc. Among them, the oncogene, FOS restrains cell-cycle entry and supports repopulating potency in human HSCs through directly binding and regulating genes both for HSC quiescence and potency. Our findings uncover the regulatory program underlying quiescence exit and highlight the critical role of FOS to guard the quiescence and potency in human HSPCs.
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Project description:Quiescence and limited dividing are critical in preserving potency of hematopoietic stem/progenitor cell (HSPCs) during lifetime, but little is known about how this process is regulated. Here, we show that the mobilized human HSPCs in peripheral blood (PB) are predominantly in a quiescent state, but rapidly exit quiescence and reduce repopulating potency in short-term culture. Through single cell RNA-seq, we identified a panel of regulators highly associated with HSC quiescence exit and cell-cycle entry. These regulators involve different biological processes such as cell-cycle, signaling pathways, metabolisms, etc. Among them, the oncogene, FOS restrains cell-cycle entry and supports repopulating potency in human HSCs through directly binding and regulating genes both for HSC quiescence and potency. Our findings uncover the regulatory program underlying quiescence exit and highlight the critical role of FOS to guard the quiescence and potency in human HSPCs.
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