The NEXT complex regulates H3K27me3 levels to affect cancer progression by degrading G4/U-Rich lncRNAs
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1199008 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31740070_1.fastq.gz | Fastqsanger.gz | |||
| SRR31740070_2.fastq.gz | Fastqsanger.gz | |||
| SRR31740071_1.fastq.gz | Fastqsanger.gz | |||
| SRR31740071_2.fastq.gz | Fastqsanger.gz | |||
| SRR31740072_1.fastq.gz | Fastqsanger.gz |
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Project description:Polycomb repressive complex 2 (PRC2) is responsible for depositing H3K27me3 and plays essential roles in gene silencing during development and cancer. Meanwhile, the nuclear exosome targeting (NEXT) complex facilitates the degradation of numerous non-coding RNAs in the nucleoplasm. Here find that the functional deficiency of the NEXT complex leads to an overall decrease in H3K27me3 levels. Specifically, ZCCHC8 depletion results in significant upregulation of nascent lncRNAs containing G-quadruplex and U-Rich motifs (G4/U-Rich lncRNAs). The G-quadruplex motif binds to EZH2, blocking the chromatin recruitment of PRC2, while the U-Rich motif is specifically recognized by the NEXT complex for RNA exosome-mediated degradation. In tumor tissues with high ZCCHC8 expression in clear cell renal cell carcinoma (ccRCC) and lung adenocarcinoma (LUAD) patients, the NEXT complex excessively degrades nascent G4/U-Rich lncRNAs. Consequently, PRC2 core subunits are released and recruited to neighboring genomic loci, resulting in increased H3K27me3 levels and downregulation of adjacent genes, including tumor suppressors like SEMA5A and ARID1A. Notably, the EZH2 inhibitor Tazemetostat (EPZ-6438) exhibits greater sensitivity in cells with higher ZCCHC8 expression. Altogether, our findings demonstrate a novel mechanism that the NEXT complex regulates H3K27me3 levels by degrading G4/U-Rich lncRNAs in cancer cells.
2025-02-24 | GSE284433 | GEO
Project description: Not available
| S-EPMC11840553 | biostudies-literature
Project description:Telomere dysfunctional CMP/GMP have deregulated pathways that are associated with DNA damage signaling We compared differentially expressed genes in the G4/G5 CMP relative to the G0 control to identify pathways that may affect CMP differentiation. Bone marrow CMP and GMP cells were sorted from two paired pools of G0 TERTER/+ or G4/G5 TERTER/ER mice (5,000-20,000 cells per sample) using the Influx Cell Sorter. Every paired pool includes CMP or GMP sorted from 4 age and gender matched G0 or G4/G5 mice. RNA from the respective sorted cells was extracted using Trizol (Ambion) and profiled on 2100 Bioanalyzer (Agilent). Gene expression profiling was performed at the Sequencing and Non-coding RNA Program at MD Anderson Cancer Center. Briefly, the GeneChip® 3 IVT Express Kit (Affymetrix) was used to generate biotin-labeled cRNA, which were purified and fragmented, before target hybridization on the GeneChip® Mouse Genome 430 2.0 Array (Affymetrix) according to the manufacturer's instructions. Affymetrix raw data (CEL files) were normalized using Affymetrix Microarray Suite (MAS) version 5.0 using a TGT=100. Paired pools used in the study were: CMP pool 1: G0-1 and G4/5-1 CMP pool 2: G0-2 and G4/G5-2 GMP pool 1: G0-1 and G4/G5-1 GMP pool 2: G0-2 and G4/G5-2
2015-04-09 | E-GEOD-62278 | biostudies-arrayexpress
Project description:Geobacillus sp. G4 strain:G4 Genome sequencing
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Project description:The RBP, FXR1, is overexpressed in many epithelial tumors containing a canonical RGG box domain. FXR1 controls post-transcriptional gene regulation through changes in mRNA turnover and translation of target genes. Here we show that arginine methyltransferase PRMT5- mediated specific arginine methylation of FXR1 increases its stability in cancer cells. FXR1-dependent gene signatures show decreased expression and instability of G4-rich sequences containing mRNAs such as CDKN1A, PLK2, TCN2, and TRAF4. Furthermore, structural features of FXR1 and G4-RNA interactions provide novel insights into the critical arginine amino acids of FXR1 essential for G4-RNA-binding and turnover activity. In addition, analysis of the eCLIP data provides various RNA targets and the G-rich sequence motifs of FXR1 in head and neck cancer cell line. Thus, our results indicate that PRMT5-mediated methylation of FXR1 binding with G4-RNAs favors mRNA stability and turnover, contributing to cancer cell growth and proliferation.
2024-04-08 | GSE252916 | GEO
Project description:Telomere dysfunctional CMP/GMP have deregulated pathways that are associated with DNA damage signaling We compared differentially expressed genes in the G4/G5 CMP relative to the G0 control to identify pathways that may affect CMP differentiation.
2015-04-09 | GSE62278 | GEO
Project description:G4 are noncanonical secondary structures consist in stacked tetrads of Hoogsteen hydrogen-bonded guanines bases. An essential feature of G-quadruplexes is their intrinsic polymorphic nature. Indeed, depending on the length and the composition of the sequence, as well as the environmental conditions (including the nature and concentration of metal cations, and local molecular crowding), a G-quadruplex-forming sequence can adopt different topologies in which the strands are in parallel or antiparallel conformations, with the co-existence of different types of loops (lateral, diagonal or propeller) with variable lengths. The impact of G4 on cellular metabolism is associated with protein or enzymatic factors that promote, inhibits or resolve these structures. Thus, the major impact of G4 on the human cell metabolism is associated with genetic defects affecting proteins that counteract their formation. Although a large number of proteins able to bind and/or "to resolve" G-quadruplex structures have been identified in vitro, less is known about their mode of interaction with G-quadruplex, their specificity versus the topology and finally their specificity for G4 structures relatively to G-rich single-stranded sequences. In this study we aimed to identify and characterize human proteins interacting with locked G4 structures.
2021-07-16 | PXD021003 | Pride
Project description:In this study we discover proteins that bind to G4 quadruplex DNA structure. We use modified c-myc quadruplex as a bait, and compare it to the control bait - T15 oligo. We use spectral counts and G-test to determine significant binders. T15 and G4 datafiles are uploaded
2016-07-07 | PXD003501 | Pride
Project description:DNA G-quadruplexes (G4s) are secondary structures with significant roles in regulating genome function and stability. Dysregulation of the dynamic formation of G4s is linked to genomic instability and disease, but the underlying mechanisms are not fully understood. In this study, we conducted a screen of chromatin-modifying enzymes and identified nine potential inhibitors of G4 formation, including seven that were not previously characterized. Among these, we highlight the role of BAZ2 chromatin remodelers as key suppressors of G4 DNA and G4-related genome instability. Depletion of BAZ2 subunits led to increased G4 formation, especially at transcriptional regulatory elements. BAZ2B was found to associate with G4 loci, suggesting that it plays a direct role in suppressing G4s. While BAZ2-deficient cells exhibited modest genomic instability, treatment with the G4-stabilizing ligand BRACO19 exacerbated double-strand breaks (DSBs), highlighting its utility as a tool to study G4-dependent genome instability. DSB profiling using INDUCE-seq uncovered distinct breakage patterns around G4s, further underscoring the impact of G4s on genome integrity. Notably, we found that within G4s, G repeats were more susceptible to DSBs than loops. These results establish BAZ2 chromatin remodeling complexes as direct regulators of G4 dynamics and provide new insights into G4-dependent genome instability.
2025-01-05 | GSE285882 | GEO
Project description:G-quadruplexes (G4s) form throughout the genome and influence important cellular processes, but their deregulation can challenge DNA replication fork progression and threaten genome stability. Here, we demonstrate an unexpected, dual role for the dsDNA translocase HLTF in G4 metabolism. First, we find that HLTF is enriched at G4s in the human genome and suppresses G4 accumulation throughout the cell cycle using its ATPase activity. This function of HLTF affects telomere maintenance by restricting alternative lengthening of telomeres, a process stimulated by G4s. We also show that HLTF and MSH2, a mismatch repair factor that binds G4s, act in independent pathways to suppress G4s and to promote resistance to G4 stabilization. In a second, distinct role, HLTF restrains DNA synthesis upon G4 stabilization by suppressing PrimPol-dependent repriming. Together, the dual functions of HLTF in the G4 response prevent DNA damage and potentially mutagenic replication to safeguard genome stability.
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