RNA expression in BRCA2-depleted breast cancer cell lines
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE116943 | GEO | 2018/12/19
REPOSITORIES: GEO
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Project description:RNA expression in BRCA2-depleted breast cancer cell lines
| PRJNA480663 | ENA
Project description:Individuals with a single functional copy of the BRCA2 tumor suppressor have elevated risks for breast, ovarian, and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to BRCA2 haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function ("BRCA2-crisis"), which may contribute to disease. Here, we establish an in vitro model for BRCA2-crisis that demonstrates chromatin remodeling and activation of an NF-κB survival pathway in response to transient BRCA2 depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation, and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These chromatin alterations are reflected in transcriptional profiles of pre-malignant tissues from BRCA2 carriers and, therefore, may reflect natural steps in human disease. By modeling BRCA2-crisis in vitro, we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies.
2019-08-07 | GSE133450 | GEO
Project description:R-loops are prevalent in mammalian genomes and involved in many fundamental cellular processes. Depletion of BRCA2 leads to aberrant R-loop accumulation, contributing to genome instability. Here, we show that ZFP281 cooperates with BRCA2 in preventing R-loop accumulation to facilitate DNA replication in embryonic stem cells. Mechanistically, we demonstrate that ZFP281 can interact with BRCA2, and that BRCA2 is enriched at G/C-rich promoters and requires both ZFP281 and PRC2 for its proper recruitment to the bivalent chromatin at the genome-wide scale. Furthermore, depletion of ZFP281 or BRCA2 leads to accumulation of R-loops over the bivalent regions, and compromises activation of the developmental genes by retinoic acid during stem cell differentiation. In summary, our results reveal that ZFP281 recruits BRCA2 to the bivalent chromatin regions to ensure proper progression of DNA replication through preventing persistent R-loops.
2022-05-31 | GSE127262 | GEO
Project description:Background: Loss of RNA Pol II transcription Mediator components like CCNC, MED12 led to improved survival of PARPi-treated and untreated BRCA2-depleted cells. Mediator is best known for its function with RNA Pol II in regulating gene transcription, we performed total mRNA-Seq with control and BRCA2-depleted CCNC- and MED12-KO cells. The aim of the present prospective study was to reveal how the gene expression is altered in both parental and BRCA2-depleted CCNC- and MED12-KO cells which might contribute to the PARPi resistance in BRCA2 depleted cells. Methods: HEK293A BRCA2 CKI mAID-EGFP WT, CCNC-KO, and MED12-KO with or without BRCA2 depletion cells (each with two biological replicates) were collected and total RNA was extracted and subjected to RNA-seq at HiSeq3000 (Illumina). Results: Based on the transcriptomic data, we examined differentially expressed genes and performed KEGG pathway enrichment analysis.The results suggested that in both control and BRCA2-depleted CCNC- and MED12-knockout cells, several signaling pathways like the transforming growth factor (TGF)-beta signaling pathway and extracellular matrix (ECM)-receptor interaction pathway et al were activated which probably facilitate cell proliferation upon BRCA2 loss. Conclusions: Our results imply that TGF-beta signaling and other signaling pathways such as the ECM-receptor interaction pathway which play roles in the regulation of cellular functions such as proliferation, adhesion, apoptosis, differentiation and migration, may together contribute to the involvement of CCNC and MED12 in drug resistance.
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Project description:We elucidated the function of the alternative Wnt receptor Ror2 in lineage-depleted tumor organoid cells, using lentiviral short hairpin RNA (shRNA)-mediated depletion.
2022-10-26 | GSE176041 | GEO
Project description:We elucidated the function of the alternative Wnt receptor Ror2 in lineage-depleted tumor organoid cells, using lentiviral short hairpin RNA (shRNA)-mediated depletion.
2022-10-26 | GSE174506 | GEO
Project description:Heterozygous germline mutations in BRCA2 predispose to breast and ovarian cancer. Contrary to non-cancerous cells, where BRCA2 deletion causes cell cycle arrest or cell death, BRCA2 inactivation in tumors is associated with uncontrolled cell proliferation. We set out to investigate this conundrum by exploring modalities of cell adaptation to loss of BRCA2 and focused on genome-wide transcriptome alterations. Human cells in which BRCA2 expression was inhibited using a doxycycline (DOX)-inducible shRNA for 4 or 28 days were subjected to RNA-seq analyses. Gene sets differentially expressed in BRCA2-deficient versus -proficient cells revealed a biphasic response to BRCA2 abrogation. The early, acute response consisted of downregulation of genes involved in cell cycle progression, DNA replication and repair and was associated with cell cycle arrest in G1. Surprisingly, the late, chronic response consisted exclusively of upregulation of innate immune response genes controlled by interferon. Activation of the cGAS-STING pathway detected in these cells further substantiated the concept that long-term BRCA2 abrogation triggers cell-intrinsic immune signaling. Importantly, we found that treatment with PARP inhibitors stimulated the interferon response in cells and tumors lacking BRCA2. We propose that PARP inhibitors suppress growth of BRCA2-deficient cells and tumors, in part, by activating interferon signaling.
2018-12-11 | GSE123631 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE32124: Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers [expression data] GSE32258: Effects of BRCA2 cis-regulation in normal breast and cancer risk amongst BRCA2 mutation carriers [SNP data] Refer to individual Series
2012-02-01 | E-GEOD-32259 | biostudies-arrayexpress
Project description:Individuals with a single functional copy of the BRCA2 tumor suppressor have elevated risks for breast, ovarian and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to BRCA2 haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function (“BRCA2-crisis”), which may contribute to disease. Here we establish an in vitro model for BRCA2-crisis that demonstrates novel epigenetic remodeling and activation of an NF-κB survival pathway in response to transient BRCA2-depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These epigenetic alterations are reflected in transcriptional profiles of pre-malignant tissues from BRCA2-carriers and therefore may reflect natural steps in human disease. By modeling BRCA2-crisis in vitro we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies.
2019-08-07 | GSE133728 | GEO
Project description:Identification of genes regulated by the transcription factor HNF4a2 Experiment Overall Design: We used microarrays to identify genes regulated by the transcription factor HNF4a2. HEK293 cell lines containing doxycyclin-inducible wilt type or mutant forms of HNF4a2m which were introduced by FRT/FLP mediated recombination into FLP-In T-REx 293 cells (Invitrogen) were treated for 24 hours with 1 µg/ml doxycyclin. Gene expression profiles of induced and noninduced cells were compared to identify HNF4 regulated targets.
2008-10-18 | E-GEOD-8289 | biostudies-arrayexpress