RSC primes the quiescent genome for hypertranscription upon cell cycle re-entry
Ontology highlight
ABSTRACT:
ORGANISM(S): Saccharomyces cerevisiae
PROVIDER: GSE166789 | GEO | 2021/02/16
REPOSITORIES: GEO
Similar Datasets
Project description:Quiescence is a reversible G0 state essential for differentiation, regeneration, stem-cell renewal, and immune cell activation. Necessary for long-term survival, quiescent chromatin is compact, hypoacetylated, and transcriptionally inactive. How transcription activates upon cell-cycle re-entry is undefined. Here we report robust, widespread transcription within the first minutes of quiescence exit. During quiescence, the chromatin-remodeling enzyme RSC was already bound to the genes induced upon quiescence exit. RSC depletion caused severe quiescence exit defects: a global decrease in RNA polymerase II (Pol II) loading, Pol II accumulation at transcription start sites, initiation from ectopic upstream loci, and aberrant antisense transcription. These phenomena were due to a combination of highly robust Pol II transcription and severe chromatin defects in the promoter regions and gene bodies. Together, these results uncovered multiple mechanisms by which RSC facilitates initiation and maintenance of large-scale, rapid gene expression despite a globally repressive chromatin state.
| S-EPMC8186906 | biostudies-literature
Project description:RSC primes the quiescent genome for hypertranscription upon cell cycle re-entry
| PRJNA701958 | ENA
Project description:Quiescent cells reside in G0 phase, which is characterized by the absence of cell growth and proliferation. These cells remain viable and re-enter the cell cycle when prompted by appropriate signals. Using a budding yeast model of cellular quiescence, we investigated the program that initiated DNA replication when these G0 cells resumed growth. We performed BrdU IP-Seq to examine the DNA replication profile genome-wide. These data revealed that the initiation of replication was delayed and fewer origins were active when G0 cells entered the cell cycle compared to the entry of G1 cells into S phase. We found that both the transcript and protein levels of these replication factors were significantly diminished during the development of proliferating cells into quiescence. The levels of these factors, including MCM2-7 helicase, increased as G0 cells re-entered the cell cycle, suggesting that the replication program is re-established de novo. Consistent with these results, Mcm4 ChIP-seq analysis showed fewer and reduced binding at a number of origins during the re-entry of G0 cells into the cell cycle. In support of this evidence, the chromatin context surrounding inactive origins of G0 cells exhibits greater increased nucleosome occupancy and reduced periodicity of nucleosome positioning. Altogether, these observations provide insights into the important role of chromatin context that determines the ability of replication origin to accrue limiting replication factors during the the re-entry of quiescent cells into the cell cycle.
2020-08-07 | GSE155831 | GEO
Project description:Cell cycle re-entry of quiescent cancer cells has been proposed to be involved in cancer progression and recurrence. Cytosolic phospholipase A2? (cPLA2?) is an enzyme that hydrolyzes membrane glycerophospholipids to release arachidonic acid and lysophospholipids that are implicated in cancer cell proliferation. The aim of this study was to determine the role of cPLA2? in cell cycle re-entry of quiescent prostate cancer cells. When PC-3 and LNCaP cells were rendered to a quiescent state, the active form of cPLA2? with a phosphorylation at Ser505 was lower compared to their proliferating state. Conversely, the phospho-cPLA2? levels were resurgent during the induction of cell cycle re-entry. Pharmacological inhibition of cPLA2? with Efipladib upon induction of cell cycle re-entry inhibited the re-entry process, as manifested by refrained DNA synthesis, persistent high proportion of cells in G0/G1 and low percentage of cells in S and G2/M phases, together with a stagnant recovery of Ki-67 expression. Simultaneously, Efipladib prohibited the emergence of Skp2 while maintained p27 at a high level in the nuclear compartment during cell cycle re-entry. Inhibition of cPLA2? also prevented an accumulation of cyclin D1/CDK4, cyclin E/CDK2, phospho-pRb, pre-replicative complex proteins CDC6, MCM7, ORC6 and DNA synthesis-related protein PCNA during induction of cell cycle re-entry. Moreover, a pre-treatment of the prostate cancer cells with Efipladib during induction of cell cycle re-entry subsequently compromised their tumorigenic capacity in vivo. Hence, cPLA2? plays an important role in cell cycle re-entry by quiescent prostate cancer cells.
| S-EPMC4741466 | biostudies-literature
Project description:Cellular quiescence is coupled with cellular development, tissue homeostasis, and cancer progression. Both quiescence and cell cycle re-entry are controlled by active and precise regulation of gene expression. However, the roles of long noncoding RNAs (lncRNAs) during these processes remain to be elucidated. By performing a genome-wide transcriptome analyses, we identify thousands of differentially expressed lncRNAs, including ~30 of the less-characterized class of microRNA-host-gene lncRNAs (lnc-MIRHGs), during cellular quiescence and during serum-stimulation in human diploid cells. We observe that the mature MIR222HG display serum-stimulated induction due to enhanced pre-RNA splicing. Serum-stimulated binding of the pre-mRNA splicing factor SRSF1 to a micro-exon, which partially overlaps with the primary miR-222 precursor, facilitates enhanced MIR222HG splicing. In serum-stimulated cells, SRSF1 negatively regulates the Drosha/DGCR8-catalyzed cleavage of pri-miR-222, thereby increasing the cellular pool of the mature MIR222HG. Further, loss-of-function studies indicate that the mature MIR222HG facilitates the serum-stimulated cell cycle re-entry in a microRNA-independent manner. Mechanistically, MIR222HG, along with ILF3/2 complex, forms RNA:RNA duplex with DNM3OS lncRNA, thereby promoting DNM3OS stability. The current study identifies a mechanism in which the interplay between splicing versus microprocessor complex dictates the serum-induced expression of lnc-MIRHG MIR222HG for efficient cell cycle re-entry.
2020-09-07 | PXD017585 | Pride
Project description:Regeneration of damaged tissues typically requires a population of active stem cells. How damaged tissue is regenerated in quiescent tissues lacking a stem cell population is less well understood. We used a genetic screen in the developing Drosophila melanogaster eye to investigate the mechanisms that trigger quiescent cells to re-enter the cell cycle and proliferate in response to tissue damage. We discovered that Hippo signaling regulates compensatory proliferation after extensive cell death in the developing eye. Scalloped and Yorkie, transcriptional effectors of the Hippo pathway, drive Cyclin E expression to induce cell cycle re-entry in cells that normally remain quiescent in the absence of damage. Ajuba, an upstream regulator of Hippo signaling that functions as a sensor of epithelial integrity, is also required for cell cycle re-entry. Thus, in addition to its well-established role in modulating proliferation during periods of tissue growth, Hippo signaling maintains homeostasis by regulating quiescent cell populations affected by tissue damage.
| S-EPMC4550963 | biostudies-literature
Project description:Hematopoietic stem cells (HSCs) maintain homeostasis and regenerate the blood system throughout life. It has been postulated that HSCs may be uniquely capable of preserving their genomic integrity in order to ensure lifelong function. To directly test this, we quantified DNA damage in HSCs and downstream progenitors from young and old mice, revealing that strand breaks significantly accrue in HSCs during aging. DNA damage accumulation in HSCs was associated with broad attenuation of DNA repair and response pathways that was dependent upon HSC quiescence. Accordingly, cycling fetal HSCs and adult HSCs driven into cycle upregulated these pathways leading to repair of strand breaks. Our results demonstrate that HSCs are not comprehensively geno-protected during aging. Rather, HSC quiescence and concomitant attenuation of DNA repair and response pathways underlies DNA damage accumulation in HSCs during aging. These results provide a potential mechanism through which premalignant mutations accrue in HSCs.
| S-EPMC4082747 | biostudies-literature
Project description:Liver regeneration and metabolism are highly interconnected. Here, we show that hepatocyte-specific ablation of RNA polymerase II (Pol II)-associated Gdown1 leads to down-regulation of highly expressed genes involved in plasma protein synthesis and metabolism, a concomitant cell cycle re-entry associated with induction of cell cycle-related genes (including cyclin D1), and up-regulation of p21 through activation of p53 signaling. In the absence of p53, Gdown1-deficient hepatocytes show a severe dysregulation of cell cycle progression, with incomplete mitoses, and a premalignant-like transformation. Mechanistically, Gdown1 is associated with elongating Pol II on the highly expressed genes and its ablation leads to reduced Pol II recruitment to these genes, suggesting that Pol II redistribution may facilitate hepatocyte re-entry into the cell cycle. These results establish an important physiological function for a Pol II regulatory factor (Gdown1) in the maintenance of normal liver cell transcription through constraints on cell cycle re-entry of quiescent hepatocytes.
| S-EPMC7263145 | biostudies-literature
Project description:Blockade of cell cycle re-entry in quiescent cancer cells is a strategy to prevent cancer progression and recurrence. We investigated the action and mode of action of CPF mixture (Coptis chinensis, Pinellia ternata and Fructus trichosanthis) in impeding a proliferative switch in quiescent lung cancer cells. The results indicated that CPF impeded cell cycle re-entry in quiescent lung cancer cells by reduction of FACT and c-MYC mRNA and protein levels, with concomitant decrease in H3K4 tri-methylation and RNA polymerase II occupancy at FACT and c-MYC promoter regions. Animals implanted with quiescent cancer cells that had been exposed to CPF had reduced tumour volume/weight. Thus, CPF suppresses proliferative switching through transcriptional suppression of FACT and the c-MYC, providing a new insight into therapeutic target and intervention method in impeding cancer recurrence.
| S-EPMC7011132 | biostudies-literature
Project description:Chromatin structure restricts origin utilization when quiescent cells re-enter the cell cycle
| PRJNA655722 | ENA