Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA379324 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR5346310.fastq.gz | Fastqsanger.gz | |||
| SRR5346320.fastq.gz | Fastqsanger.gz | |||
| SRR5346330.fastq.gz | Fastqsanger.gz | |||
| SRR5346340.fastq.gz | Fastqsanger.gz | |||
| SRR5346311.fastq.gz | Fastqsanger.gz |
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Project description:Most BRCA1-associated breast tumors are basal-like yet originate from luminal progenitor cells. BRCA1 is best known for its functions in DNA repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions of BRCA1 fully explains the cell lineage-specific increase in breast tumor development. Cell culture-based studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcriptional regulation and genetic instability. We found that BRCA1 mutation-associated R-loop accumulates preferentially in luminal epithelial cells of cancer-free human breast tissue, and at the 5' end of those genes that experience promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of mouse NELF-B/COBRA1, a Pol II-pausing factor and BRCA1-binding protein, in Brca1 knockout mouse mammary epithelium ameliorates R-loop accumulation and reduces mammary tumorigenesis. Our studies show that Pol II pausing is a previously unappreciated contributor to BRCA1-associated R-loop accumulation and breast cancer development.
2017-06-27 | GSE96672 | GEO
Project description:BRCA1 primarily functions to maintain genomic integrity; therefore, mutations in BRCA1 are associated with increased risk of developing breast (≥70%) and ovarian (≥40%) cancers. Additionally, tumors arising from BRCA1 mutations are typically high grade and recurrent in nature. Thus, there is an urgent need to identify novel optimal therapeutic options for the majority of these patients. Herein, we performed a targeted CRISPR-Cas9 dropout screen and identified Methylphosphate Capping Enzyme, MEPCE, as a potential synthetic lethal interactor of BRCA1. Mechanistically, depletion of MEPCE in a BRCA1-deficient setting results in increased RNA polymerase II redistribution, R-loop accumulation, as well as replication stress, concomitantly contributing to transcription-replication collision events. These factors compromise genomic integrity, thereby resulting in loss of viability of BRCA1-deficient tumor cells. We also identified RNA polymerase II-associated factor I, PAF1, as a synthetic lethal interactor of BRCA1. Similar to MEPCE depletion, loss of PAF1 in a BRCA1-deficient setting results in R-loop accumulation, transcription-replication conflicts, and cell death. Our study highlights the dependence of BRCA1-defective tumors on factors such as MEPCE and PAF1 that suppress transcription-replication conflicts through RNAPII pausing and release regulation to maintain genomic stability. This highlights the untapped potential of factors such as MEPCE as novel therapeutic targets for the treatment of cancers associated with BRCA1 mutations.
2023-04-25 | GSE173223 | GEO
Project description:Work from our mouse models showed that COBRA1, the B subunit of NELF, could facilitate R-loop (DNA:RNA hybrid) accumulation in the BRCA1-deficient mouse mammary epithelium. Since NELF could promoter RNA PolII pausing at promoter proximal regions, we asked whether COBRA1-mediated RNA Pol II pausing could contribute to accumulated R-loops. To answer this question, we performed chromatin immunoprecipitation-sequencing (ChIP-seq) for RNA Pol II, as well as two NELF subunits, NELF-A and NELF-B (COBRA1) in mouse primary mammary epithelium cells. To locate R-loops in the same cell population, we performed DNA:RNA immunoprecipitation-sequencing (DRIP-seq) with or without treatment of RNase H, a nuclease that specifically degrades RNA in the R-loop structure. Our sequencing results showed that RNA Pol II, NELF and R-loops are all enriched at transcription start sites (TSSs). Notably, genes with TSS R-loop accumulation are significantly enriched for COBRA1 binding. Taken together, the genomic data lent additional support to the notion that COBRA1-mediated RNAPII pausing contributes to R-loop dynamics in mammary epithelium.
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Project description:Breast cancer linked with BRCA1/2 mutations commonly recur and resist current therapies, including PARP inhibitors. Given the lack of effective targeted therapies for BRCA1-mutant cancers, we sought to identify novel targets to selectively kill these cancers. Here, we report that loss of RNF8 significantly protects Brca1-mutant mice against mammary tumorigenesis. RNF8 deficiency in human BRCA1-mutant breast cancer cells was found to promote R-loop accumulation and replication fork instability, leading to increased DNA damage, senescence, and synthetic lethality. Mechanistically, RNF8 interacts with XRN2, which is crucial for transcription termination and R-loop resolution. We report that RNF8 ubiquitylates XRN2 to facilitate its recruitment to R-loop-prone genomic loci and that RNF8 deficiency in BRCA1-mutant breast cancer cells decreases XRN2 occupancy at R-loop-prone sites, thereby promoting R-loop accumulation, transcription-replication collisions, excessive genomic instability, and cancer cell death. Collectively, our work identifies a synthetic lethal interaction between RNF8 and BRCA1, which is mediated by a pathological accumulation of R-loops.
2023-09-14 | GSE202723 | GEO
Project description:We analyzed the breadth and functional relationships of RNA Polymerase II pausing across many human and mouse cell types to understand what roles RNA Polymerase II pausing plays in gene regulation. We identified a novel association of H2A.Z at the TSS of increasingly paused genes. We knocked down H2A.Z to test whether H2A.Z positively or negatively affects RNA Polymerase II pausing to find that pausing globally increased upon knockdown.
2016-04-28 | GSE60872 | GEO
Project description:Promoter-proximal RNA polymerase II (Pol II) pausing is implicated in the regulation of gene transcription. However, the mechanisms of pausing including its dynamics during transcriptional responses remain to be fully understood. We performed global analysis of short capped RNAs and Pol II Chromatin Immunoprecipitation sequencing in MCF-7 breast cancer cells to map Pol II pausing across the genome, and used permanganate footprinting to specifically follow pausing during transcriptional activation of several genes involved in the Epithelial to Mesenchymal Transition (EMT). We find that the gene for EMT master regulator Snail (SNAI1), but not Slug (SNAI2), shows evidence of Pol II pausing before activation. Transcriptional activation of the paused SNAI1 gene is accompanied by a further increase in Pol II pausing signal whereas activation of non-paused SNAI2 gene results in the acquisition of a typical pausing signature. The increase in pausing signal reflects increased transcription initiation without changes in Pol II pausing. Activation of the heat shock HSP70 gene involves pausing release that speeds up Pol II turnover, but does not change pausing location. We suggest that Pol II pausing is retained during transcriptional activation and can further undergo regulated release in a signal-specific manner. Untreated MCF-7 cells were analyzed for the distribution of Pol II using ChIP-sequencing with Anti-Pol II N-20 antibody (two independent biological replicates, A, B), and for the distribution of paused RNA polymerase II by sequencing of short capped RNAs (scRNAs) prepared from nuclei (three independent biological replicates, 1-3). All samples were sequenced on a MiSeq instrument in paired-end format
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Project description:Kras is the most commonly mutated oncogene in human cancer and mutant Kras is responsible for over 90% of pancreatic ductal adnocarcinoma (PDAC), the most leath cancer. Here, we identified that RNA polymerase II associated factor 1 complex (PAF1C) is specifically required for the survival of PDAC but not normal adult panreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining the over accumulation of enhancer RNAs (eRNAs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of eRNAs on chromatin and therby abbarrent R-loop formation, TC-NER pathway activation and double stranded DNA breaks, which in turn trigger cell death. We also demonstrate that the sepcific demand for PAF1C by cancer cells is due to the global activation of enhancers and thus eRNA transcription during tumorigenesis. The work provides a novel insight in how transcription addiction is caused during tumorigenesis.
2023-11-01 | GSE217744 | GEO
Project description:Kras is the most commonly mutated oncogene in human cancer and mutant Kras is responsible for over 90% of pancreatic ductal adnocarcinoma (PDAC), the most leath cancer. Here, we identified that RNA polymerase II associated factor 1 complex (PAF1C) is specifically required for the survival of PDAC but not normal adult panreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining the over accumulation of enhancer RNAs (eRNAs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of eRNAs on chromatin and therby abbarrent R-loop formation, TC-NER pathway activation and double stranded DNA breaks, which in turn trigger cell death. We also demonstrate that the sepcific demand for PAF1C by cancer cells is due to the global activation of enhancers and thus eRNA transcription during tumorigenesis. The work provides a novel insight in how transcription addiction is caused during tumorigenesis.
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Project description:Kras is the most commonly mutated oncogene in human cancer and mutant Kras is responsible for over 90% of pancreatic ductal adnocarcinoma (PDAC), the most leath cancer. Here, we identified that RNA polymerase II associated factor 1 complex (PAF1C) is specifically required for the survival of PDAC but not normal adult panreatic cells. We show that PAF1C maintains cancer cell genomic stability by restraining the over accumulation of enhancer RNAs (eRNAs) driven by mutant Kras. Loss of PAF1C leads to cancer-specific lengthening and accumulation of eRNAs on chromatin and therby abbarrent R-loop formation, TC-NER pathway activation and double stranded DNA breaks, which in turn trigger cell death. We also demonstrate that the sepcific demand for PAF1C by cancer cells is due to the global activation of enhancers and thus eRNA transcription during tumorigenesis. The work provides a novel insight in how transcription addiction is caused during tumorigenesis.
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