Super-enhancer Acquisition Drives Oncogene Expression in Triple Negative Breast Cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB33558 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR3443990.fastq.gz | Fastqsanger.gz | |||
| ERR3445580.fastq.gz | Fastqsanger.gz | |||
| ERR3445582.fastq.gz | Fastqsanger.gz | |||
| ERR3445573.fastq.gz | Fastqsanger.gz | |||
| ERR3444454.fastq.gz | Fastqsanger.gz |
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Project description:Here we apply integrated epigenomic and transcriptomic profiling to uncover super-enhancer heterogeneity between breast cancer subtypes, and provide clinically relevant biological insights towards TNBC. Using CRISPR/Cas9-mediated gene editing, we identify genes that are specifically regulated by TNBC-specific super-enhancers, including FOXC1 and MET, thereby unveiling a mechanism for specific overexpression of the key oncogenes in TNBC. We also identify ANLN as a novel TNBC-specific gene regulated by super-enhancer. Our studies reveal a TNBC-specific epigenomic landscape, contributing to the dysregulated oncogene expression in breast tumorigenesis.
2021-03-04 | PXD024505 |
Project description:Triple Negative Breast Cancer (TNBC) is a heterogeneous disease lacking known molecular drivers and effective targeted therapies. Cytotoxic chemotherapy remains the mainstay of treatment for TNBCs, which have significantly poorer survival rates compared to other breast cancer subtypes. In addition to changes within the coding genome, aberrant enhancer activity is a well-established contributor to tumorigenesis. Here we use H3K27Ac chromatin immunoprecipitation followed by sequencing (ChIP-Seq) to map the active cis-regulatory landscape in TNBC. We identify distinct disease subtypes associated with specific enhancer activity, and over 2,500 unique superenhancers acquired by tumor cells but absent from normal breast tissue. To identify potential actionable disease drivers, we probed the dependency on genes that associate with tumor-specific enhancers by CRISPR screening. In this way we identify a number of tumor-specific dependencies, including a previously uncharacterized dependency on the TGFβ pseudo-receptor BAMBI.
| S-EPMC7316302 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is the most therapeutically recalcitrant form of breast cancer. Pioneering genomic studies have identified the repertoire of expressed genes in the distinct molecular subtypes of breast cancer and have been instrumental in providing diagnostic, prognostic, and therapeutic guidance. Yet breast cancer remains the second leading cause of cancer mortality in women. This is due, in part, to the paucity of targeted therapies for triple-negative breast cancer (TNBC). We posit that a systematic analysis of regulatory elements that extend beyond protein coding genes will lead to novel avenues for therapeutic intervention. To this end, we analyzed the regulatory mechanisms of TNBC-specific transcriptional enhancers together with their non-coding enhancer RNA (eRNA) transcripts. We systematically probed the functions of the top 30 eRNA-producing super-enhancers using a high-throughput CRISPR-interference (dCas9-KRAB) assay coupled to RNA-seq that enabled unbiased detection of target genes genome-wide. Utilizing Hi-C, we constructed 3D chromatin interaction maps to annotate direct target genes for each super-enhancer and highlight their proclivity for genes that portend worse clinical outcomes in TNBC patients. To illustrate the utility of this dataset, we selected a novel super-enhancer controlling the nearby PODXL gene and demonstrate that deletion of the super-enhancer (via Cas9 deletion) or specific degradation of its enhancer RNAs (via Cas13 RNA cleavage) leads to profound effects on target gene expression, cell proliferation, and migration. Furthermore, complete knockout of the PODXL super-enhancer leads to a significant decrease in tumor growth and metastatic potential in mouse xenograft experiments. Collectively, this work examines several fundamental questions about how regulatory information encoded into eRNA-producing super-enhancers drives gene expression networks that underlie the biology of triple-negative breast cancer.
2024-08-14 | GSE234324 | GEO
Project description:Triple-negative breast cancer (TNBC) is the most therapeutically recalcitrant form of breast cancer. Pioneering genomic studies have identified the repertoire of expressed genes in the distinct molecular subtypes of breast cancer and have been instrumental in providing diagnostic, prognostic, and therapeutic guidance. Yet breast cancer remains the second leading cause of cancer mortality in women. This is due, in part, to the paucity of targeted therapies for triple-negative breast cancer (TNBC). We posit that a systematic analysis of regulatory elements that extend beyond protein coding genes will lead to novel avenues for therapeutic intervention. To this end, we analyzed the regulatory mechanisms of TNBC-specific transcriptional enhancers together with their non-coding enhancer RNA (eRNA) transcripts. We systematically probed the functions of the top 30 eRNA-producing super-enhancers using a high-throughput CRISPR-interference (dCas9-KRAB) assay coupled to RNA-seq that enabled unbiased detection of target genes genome-wide. Utilizing Hi-C, we constructed 3D chromatin interaction maps to annotate direct target genes for each super-enhancer and highlight their proclivity for genes that portend worse clinical outcomes in TNBC patients. To illustrate the utility of this dataset, we selected a novel super-enhancer controlling the nearby PODXL gene and demonstrate that deletion of the super-enhancer (via Cas9 deletion) or specific degradation of its enhancer RNAs (via Cas13 RNA cleavage) leads to profound effects on target gene expression, cell proliferation, and migration. Furthermore, complete knockout of the PODXL super-enhancer leads to a significant decrease in tumor growth and metastatic potential in mouse xenograft experiments. Collectively, this work examines several fundamental questions about how regulatory information encoded into eRNA-producing super-enhancers drives gene expression networks that underlie the biology of triple-negative breast cancer.
2024-08-14 | GSE234323 | GEO
Project description:Triple-negative breast cancer (TNBC) is a highly aggressive form of breast cancer that exhibits extremely high levels of genetic complexity and yet a relatively uniform transcriptional program. We postulate that TNBC might be highly dependent on uninterrupted transcription of a key set of genes within this gene expression program and might therefore be exceptionally sensitive to inhibitors of transcription. Utilizing a novel kinase inhibitor and CRISPR/Cas9-mediated gene editing, we show here that triple-negative but not ER/PR+ breast cancer cells are exceptionally dependent on CDK7, a transcriptional cyclin-dependent kinase. TNBC cells are unique in their dependence on this transcriptional CDK and suffer apoptotic cell death upon CDK7 inhibition. An “Achilles cluster” of TNBC-specific genes are extremely sensitive to CDK7 inhibition and frequently associated with super-enhancers. We conclude that CDK7 mediates transcriptional addiction to a vital cluster of genes in TNBC and CDK7 inhibition may be useful therapy for this challenging cancer. Expression microarrays in H3K27ac in triple-negative breast cancer +/- treatment with covalent CDK7 inhibitor THZ1 treatment
2015-09-24 | E-GEOD-69106 | biostudies-arrayexpress
Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor prognosis. The high malignancy of TNBC is contributed by its heterogeneity and enrichment of cancer stem cells. By performing multiomic profiling, we recently uncovered super-enhancer heterogeneity between breast cancer subtypes. Here, we identify TCOF1 as a novel super-enhancer-regulated gene that promotes TNBC growth and stemness. TCOF1, which plays a critical role in craniofacial development, is frequently upregulated in TNBC and its elevated expression correlates with shorter overall survival. Whereas TCOF1 depletion has potent effects on the growth and stemness of basal-like TNBC, it has no effect on mesenchymal-like cells, highlighting the distinct molecular dependency in different subgroups of TNBC. Whole genome RNA sequencing uncovers several stem cell molecules regulated by TCOF1. We further demonstrate that the upregulation of KIT by TCOF1 mediates TNBC stemness. These findings provide a rationale for developing therapeutics targeting TCOF1 in basal-like TNBC.
2021-11-02 | GSE168835 | GEO
Project description:Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes, and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs are more similar to mesenchymal neuroblastoma and rhabdoid tumors than to other TNBC subtypes, and the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming cellular super-enhancer landscapes and transcriptome but it is not required for its maintenance and for cellular viability. Our comprehensive, large scale, multi-platform, multi-omics study of both experimental and clinical TNBC is an excellent resource for the scientific and clinical research communities as it opens new venues for future investigations.
2023-01-17 | MSV000091071 | MassIVE
Project description:Using GRO-Seq, we find extensive regulation of enhancer RNAs (eRNA) within super-enhancers in response to lipopolysaccharide treatment in macrophages. Both activation and repression of gene expression are associated with super-enhancers and eRNA transcription dynamics. Co-treatment of LPS and the anti-inflammatory drug dexamethasone targeted specific super-enhancers by attenuating their eRNA expression, leading to reduced expression of key inflammatory genes. We propose that super-enhancers function as molecular rheostats integrating the binding profiles of key regulators to produce dynamic profiles of gene expression. Nascent transcriptome (GRO-Seq) analysis over a time course (0, 20, 60, 180 min) of Lipopolisaccharide and Dexamethasone signaling in mouse bone marrow-derived macrophages.
2014-12-25 | E-GEOD-60857 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. ChIP-seq in parental and JQ1 resistant triple negative breast cancer (TNBC) in response to DMSO or JQ1 treatment
2016-01-07 | E-GEOD-63581 | biostudies-arrayexpress
Project description:Triple negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. Here we report the preferential and high sensitivity of TNBCs to BET bromodomain inhibitors such as JQ1 manifested by cell cycle arrest in early G1, apoptosis, and induction of markers of luminal epithelial differentiation in vitro and in vivo. The sensitivity of TNBC and other tumor types to BET inhibition establishes a rationale for clinical investigation, and a motivation to understand mechanisms of resistance. After engendering acquired resistance to BET inhibition in previously sensitive TNBCs, we utilized integrative approaches to identify a unique mechanism of epigenomic resistance to this epigenetic therapy. Resistant cells remain dependent on BRD4, confirmed by RNA interference. However, TNBC cells adapt to BET bromodomain inhibition by re-recruitment of unmutated BRD4 to super-enhancers, now in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify hyper-phosphorylation of BRD4 and strong association with MED1. Together, these studies provide a rationale for BET inhibition in TNBC and argue for combination strategies to anticipate clinical drug resistance. Chem-Seq in parental and JQ1 resistant triple negative breast cancer (TNBC)
2016-01-07 | E-GEOD-63284 | biostudies-arrayexpress