CSTF2 mediated mRNA N6-methyladenosine modification drives pancreatic ductal adenocarcinoma m6A subtypes

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 10, 2023

Abstract N 6 - methyladenosine (m A) modification of gene transcripts plays critical roles in cancer. Here we report transcriptomic m A profiling 98 tissue samples from 65 individuals with pancreatic ductal adenocarcinoma (PDAC). We identify 17,996 peaks 195 hyper-methylated and 93 hypo-methylated PDAC compared adjacent normal tissues. The differential modifications distinguish two subtypes different prognosis outcomes. formation the is driven by a newly identified regulator CSTF2 that co-transcriptionally regulates installation through slowing RNA Pol II elongation rate during transcription. find most CSTF2-regulated As have positive effects on level host genes, are mainly recognized IGF2BP2, an reader stabilizes mRNAs. These results provide promising subtyping strategy potential therapeutic targets for precision medicine PDAC.

Language: Английский

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Approaches to probe and perturb long noncoding RNA functions in diseases

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 85, P. 102158 - 102158

Published: Feb. 26, 2024

Long noncoding RNAs (lncRNAs) are a class of RNA molecules exceeding 200 nucleotides in length that lack long open-reading frames. Transcribed predominantly by polymerase II (>500nt), lncRNAs can undergo splicing and produced from various regions the genome, including intergenic regions, introns, antisense orientation to protein-coding genes. Aberrations lncRNA expression or function have been associated with wide variety diseases, cancer, cardiovascular diabetes, neurodegeneration. Despite growing recognition select as key players cellular processes several challenges obscure comprehensive understanding their functional landscape. Recent technological innovations, such sequencing, affinity-based techniques, imaging, perturbation, advanced characterization mechanistic disease-associated lncRNAs.

Language: Английский

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Acute depletion of human core nucleoporin reveals direct roles in transcription control but dispensability for 3D genome organization

Cell Reports, Journal Year: 2022, Volume and Issue: 41(5), P. 111576 - 111576

Published: Nov. 1, 2022

The nuclear pore complex (NPC) comprises more than 30 nucleoporins (NUPs) and is a hallmark of eukaryotes. NUPs have been suggested to be important in regulating gene transcription 3D genome organization. However, evidence support their direct roles remains limited. Here, by Cut&Run, we find that core display broad but also cell-type-specific association with active promoters enhancers human cells. Auxin-mediated rapid depletion two demonstrates NUP93, not NUP35, directly specifically controls transcription. NUP93 activates genes high levels RNA polymerase II loading transcriptional elongation facilitating full BRD4 recruitment enhancers. dCas9-based tethering confirms causal role activation. Unexpectedly, situ Hi-C H3K27ac or H3K4me1 HiChIP results upon acute show negligible changesS2211-1247(22)01437-1 organization ranging from A/B compartments topologically associating domains (TADs) enhancer-promoter contacts.

Language: Английский

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LINE-1 repression in Epstein–Barr virus-associated gastric cancer through viral–host genome interaction

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(10), P. 4867 - 4880

Published: March 12, 2023

Long INterspersed Element 1 (LINE-1 or L1) acts as a major remodeling force in genome regulation and evolution. Accumulating evidence shows that virus infection impacts L1 expression, potentially impacting host antiviral response diseases. The underlying mechanism is unclear. Epstein-Barr (EBV), double-stranded DNA linked to B-cell epithelial malignancies, known have viral-host interaction, resulting transcriptional rewiring EBV-associated gastric cancer (EBVaGC). By analyzing publicly available datasets from the Gene Expression Omnibus (GEO), we found EBVaGC has repression compared with EBV-negative (EBVnGC). More specifically, retrotransposition-associated young full-length L1s (FL-L1s) were among most repressed L1s. Epigenetic alterations, especially increased H3K9me3, observed on FL-L1s. H3K9me3 deposition was attributed TASOR key component of human silencing hub (HUSH) complex for H3K9 trimethylation. 4C- HiC-seq data indicated viral interacted proximity enhancer, strengthening loop formation between enhancer its promoter. These results EBV associated deposition, leading repression. This study uncovers expression by chromatin topology interaction EBVaGC.

Language: Английский

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Evolutionary dynamics between transposable elements and their host genomes: mechanisms of suppression and escape

Current Opinion in Genetics & Development, Journal Year: 2023, Volume and Issue: 82, P. 102092 - 102092

Published: July 28, 2023

Transposable elements (TEs) are ubiquitous among eukaryotic species. Their evolutionary persistence is likely due to a combination of tolerogenic, evasive/antagonistic, and cooperative interactions with their host genomes. Here, we focus on metazoan species review recent advances related the harmful effects TE insertions, including how epigenetic TE-derived RNAs can damage cells. We discuss new findings pathways that silence TEs, such as piRNA pathway APOBEC3 Kruppel-associated box zinc finger gene families. Finally, summarize novel strategies used by TEs evade silencing, Y chromosome permissive niche for mobilization counterdefense block silencing factors.

Language: Английский

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