Similar Datasets
Project description:Requirement for TP73 in cancer cell maintenance and genetic alterations originating from its intragenic super-enhancer
| PRJNA751059 | ENA
Project description:Recent identification of an enhancer element, RD(INK4/ARF) (RD), in the prominent INK4/ARF locus provides a novel mechanism to simultaneously regulate the transcription of p15(INK4B) (p15), p14(ARF) , and p16(INK4A) (p16) tumor suppressor genes. While genetic inactivation of p15, p14(ARF) , and p16 in human tumors has been extensively studied, little is known about genetic alterations of RD and its impact on p15, p14(ARF) , and p16 in human cancer. The purpose of this study was to investigate the potential existence of genetic alterations of RD in human cancer cells. DNAs extracted from 17 different cancer cell lines and 31 primary pheochromocytoma tumors were analyzed for deletion and mutation of RD using real-time PCR and direct DNA sequencing. We found that RD was deleted in human cancer cell lines and pheochromocytoma tumors at frequencies of 41.2% (7/17) and 13.0% (4/31), respectively. While some of these RD deletion events occurred along with deletions of the entire INK4/ARF locus, other RD deletion events were independent of genetic alterations in p15, p14(ARF) , and p16. Furthermore, the status of RD was poorly associated with the expression of p15, p14(ARF) , and p16 in tested cancer cell lines and tumors. This study demonstrates for the first time that deletion of the RD enhancer is a prevalent event in human cancer cells. Its implication in carcinogenesis remains to be further explored.
| S-EPMC5557374 | biostudies-other
Project description:Osteosarcoma (OS) is a common type of bone tumor for which there has been limited therapeutic progress over the past three decades. The prevalence of transcriptional addiction in cancer cells emphasizes the biological significance and clinical relevance of super-enhancers. In this study, we found that Max-like protein X (MLX), a member of the Myc-MLX network, is driven by super-enhancers. Upregulation of MLX predicts a poor prognosis in osteosarcoma. Knockdown of MLX impairs growth and metastasis of osteosarcoma in vivo and in vitro. Transcriptomic sequencing has revealed that MLX is involved in various metabolic pathways (e.g., lipid metabolism) and can induce metabolic reprogramming. Furthermore, knockdown of MLX results in disturbed transport and storage of ferrous iron, leading to an increase in the level of cellular ferrous iron and subsequent induction of ferroptosis. Mechanistically, MLX regulates the glutamate/cystine antiporter SLC7A11 to promote extracellular cysteine uptake required for the biosynthesis of the essential antioxidant GSH, thereby detoxifying reactive oxygen species (ROS) and maintaining the redox balance of osteosarcoma cells. Importantly, sulfasalazine, an FDA-approved anti-inflammatory drug, can inhibit SLC7A11, disrupt redox balance, and induce massive ferroptosis, leading to impaired tumor growth in vivo. Taken together, this study reveals a novel mechanism in which super-enhancer-driven MLX positively regulates SLC7A11 to meet the alleviated demand for cystine and maintain the redox balance, highlighting the feasibility and clinical promise of targeting SLC7A11 in osteosarcoma.
| S-EPMC10352384 | biostudies-literature
Project description:Many genes determining cell identity are regulated by clusters of Mediator-bound enhancer elements collectively referred to as super-enhancers. These super-enhancers have been proposed to manifest higher-order properties important in development and disease. Here we report a comprehensive functional dissection of one of the strongest putative super-enhancers in erythroid cells. By generating a series of mouse models, deleting each of the five regulatory elements of the α-globin super-enhancer individually and in informative combinations, we demonstrate that each constituent enhancer seems to act independently and in an additive fashion with respect to hematological phenotype, gene expression, chromatin structure and chromosome conformation, without clear evidence of synergistic or higher-order effects. Our study highlights the importance of functional genetic analyses for the identification of new concepts in transcriptional regulation.
| S-EPMC5058437 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-06-02 | E-GEOD-78835 | biostudies-arrayexpress
Project description:RNA sequencing of HCT116 colon cancer cells following single and combined depletions of Mediator kinase module subunits CDK8, CDK19, MED12, MED13 and MED13L and the BET family protein BRD4. The results provide insight into the shared and specific functions of kinase module subunits and BRD4 in regulation of expression of transcriptional programs including genes associated with cancer acquired super-enhancers.
2018-04-02 | E-MTAB-5873 | biostudies-arrayexpress
Project description:Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells. Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G>T is the most highly associated variant (combined P = 7.47 × 10(-29), odds ratio 0.65, 95% confidence interval 0.60-0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding (P < 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P < 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells.
| S-EPMC4775078 | biostudies-literature
Project description:Due to the lack of effective early diagnostic measures and treatment methods, bladder cancer has become a malignant tumor that seriously threatens people's lives and health. Here, we reported that LINC00162, a super-enhancer long noncoding RNA, was highly expressed in bladder cancer cells and tissues. And LINC00162 was negatively correlated with neighboring PTTG1IP expression. Knocking down LINC00162 expression can inhibit the proliferative activity of bladder cancer cells and the growth of transplanted tumors in vivo, while knocking down the expression of PTTG1IP could restore the proliferative activity of bladder cancer cells. In addition, both LINC00162 and PTTG1IP were found to be able to bind to THRAP3, a transcription-related protein. And THRAP3 can regulate PTTG1IP expression. Finally, we demonstrated a mechanism that LINC00162 could regulate PTTG1IP expression through binding THRAP3. This study provided a potential target molecule for clinical treatment of bladder cancer.
| S-EPMC7736918 | biostudies-literature
Project description:Although enhancers play critical roles in cancer, quantifying enhancer activities in clinical samples remains challenging, especially for super-enhancers. Enhancer activities can be inferred from enhancer RNA (eRNA) signals, which requires enhancer transcription loci definition. Only a small proportion of human eRNA loci has been precisely identified, limiting investigations of enhancer-mediated oncogenic mechanisms. Here, we characterize super-enhancer regions using aggregated RNA sequencing (RNA-seq) data from large cohorts. Super-enhancers usually contain discrete loci featuring sharp eRNA expression peaks. We identify >300,000 eRNA loci in ∼377 Mb super-enhancer regions that are regulated by evolutionarily conserved, well-positioned nucleosomes and are frequently dysregulated in cancer. The eRNAs provide explanatory power for cancer phenotypes beyond that provided by mRNA expression through resolving intratumoral heterogeneity with enhancer cell-type specificity. Our study provides a high-resolution map of eRNA loci through which super-enhancer activities can be quantified by RNA-seq and a user-friendly data portal, enabling a broad range of biomedical investigations.
| S-EPMC7658066 | biostudies-literature
Project description:Genetic variants associated with autism spectrum disorders (ASDs) are enriched for genes encoding synaptic proteins and chromatin regulators. Although the role of synaptic proteins in ASDs is well studied, the mechanism by which disruptions of chromatin regulators promote the development of ASDs remains unclear. Here we identify 184 neuronal long genes containing super-enhancer-like chromatin modifications across their gene bodies, which we term SE long genes. We show that SE long genes exhibit reduced transcriptional RNA Polymerase II pausing, higher transcription initiation frequency, and higher expression levels. The gene body regions of SE long genes display active epigenomic status and are organized into a highly connected chromatin unit. Notably, SE long genes are enriched in known ASD-associated genes related to the synapse and signaling pathways. These characteristics present a molecular link between chromatin regulators and synaptic function, and suggest a mechanism by which disruptions in these chromatin regulators compromise the synapse. Indeed, we show that the expression of SE long genes is more sensitive to the disruptions of autism-risk chromatin regulators, including Kmt2c, Kdm5c, Kdm6b, and Mecp2, than non-SE long genes. We propose that the transcriptional impairment of SE long genes by dysfunctional chromatin regulators is a general molecular mechanism for ASD pathogenesis.
2018-05-02 | GSE104576 | GEO