Similar Datasets
Project description:Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across primary GBM biopsies, normal brain tissues, and cell line counterparts. Analysis of differentially regulated enhancers, especially super-enhancers between GBM and normal brain tissues, as well as among GBM samples with matched RNA-sequencing data, uncovered unrecognized layers of oncogenic core transcriptional dependency and inter-tumor heterogeneity. Moreover, we demonstrate the functional relevance of leading candidates of super-enhancer-driven transcriptional factors, long non-coding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, our integrative study provides clinically relevant insights into GBM molecular classification, pathogenesis, and therapeutic innovations.
2021-05-05 | GSE145645 | GEO
Project description:Here, by mapping H3K27ac deposition, we analyze the active regulatory landscapes across primary GBM biopsies, normal brain tissues, and cell line counterparts. Analysis of differentially regulated enhancers, especially super-enhancers between GBM and normal brain tissues, as well as among GBM samples with matched RNA-sequencing data, uncovered unrecognized layers of oncogenic core transcriptional dependency and inter-tumor heterogeneity. Moreover, we demonstrate the functional relevance of leading candidates of super-enhancer-driven transcriptional factors, long non-coding RNAs, and druggable targets in GBM. Through profiling of transcriptional enhancers, our integrative study provides clinically relevant insights into GBM molecular classification, pathogenesis, and therapeutic innovations.
2021-05-05 | GSE145644 | GEO
Project description:Enhancer profiling of glioblastoma uncovers core oncogenic dependency and therapeutic opportunity
| PRJNA607789 | ENA
Project description:Enhancer profiling of glioblastoma uncovers core oncogenic dependency and therapeutic opportunity [RNA-seq]
| PRJNA607792 | ENA
Project description:Enhancer profiling of glioblastoma uncovers core oncogenic dependency and therapeutic opportunity [ChIP-seq]
| PRJNA607793 | ENA
Project description:Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy. The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations. Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes. More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1). Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.
| S-EPMC5993422 | biostudies-literature
Project description:Deregulation of transcription is a hallmark of acute myeloid leukemia (AML) that drives oncogenic expression programs and presents opportunities for therapeutic targeting. By integrating comprehensive pan-cancer enhancer landscapes with genetic dependency mapping, we find that AML-enriched enhancers encode for more selective tumor dependencies. We hypothesized that this approach could identify actionable dependencies downstream of oncogenic driver events and discovered a MYB-regulated AML-enriched enhancer regulating SEPHS2, a key component of the selenoprotein production pathway. Using a combination of patient samples and mouse models, we show that this enhancer upregulates SEPHS2, promoting selenoprotein production and antioxidant function required for AML survival. SEPHS2 and other selenoprotein pathway genes are required for AML growth in vitro. SEPHS2 knockout and selenium dietary restriction significantly delay leukemogenesis in vivo with little effect on normal hematopoiesis. These data validate the utility of enhancer mapping in target identification and suggest that selenoprotein production is an actionable target in AML.
| S-EPMC8903199 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-11-01 | E-GEOD-70047 | biostudies-arrayexpress
Project description:Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Here, we mapped active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts. Enhancer regions revealed novel oncogenes, molecular targets, and pathways, which when subjected to small molecule inhibitor or shRNA treatment, increased survival and slowed proliferation in mouse and neurosphere patient-derived models of ependymomas. This study represents one of the largest enhancer mapping study of any cancer type to date, and provides a framework for target and drug discovery for other cancers recalcitrant to therapeutic development because of their lack of known genetic drivers.
| EGAS00001002696 | EGA
Project description:Cancer is driven by both genetic and epigenetic changes that impact on gene expression profiles and the resulting tumourigenic phenotype. Enhancers are transcriptional regulatory elements that are key to our understanding of how this rewiring of gene expression is achieved in cancer cells. Here, we have harnessed the power of RNA-seq data from hundreds of patients with oesophageal adenocarcinoma (OAC) or its precursor state Barrett's oesophagus coupled with open chromatin maps to identify potential enhancer RNAs and their associated enhancer regions in this cancer. We identify ~1000 OAC-specific enhancers and use these data to uncover new cellular pathways that are operational in OAC. Among these are enhancers for JUP, MYBL2, and CCNE1, and we show that their activity is required for cancer cell viability. We also demonstrate the clinical utility of our dataset for identifying disease stage and patient prognosis. Our data therefore identify an important set of regulatory elements that enhance our molecular understanding of OAC and point to potential new therapeutic directions.
| S-EPMC9998086 | biostudies-literature