Similar Datasets
Project description:We interrogated global super-enhancer landscape and sought to discover master regulators governing the liver metastasis of colorectal cancer (CRC). Using de novo analysis, we predicted motif enrichment of master transcription factor in super-enhancers. We show that transcription factor-binding sites of hepatocyte nuclear factor 1 (HNF1) family are enriched at super-enhancers identified in cell lines derived from liver metastases, but not those derived from primary tumors. Using ChIP-Seq of acetylated H3K27, the enrichment of HNF1 binding motifs in super enhancers was found in a cell line derived from xenografted liver metastasis but not the parental cell line. The prediction method was further extended to pancreatic cancer where liver metastasis is also a common finding, and a similar enrichment of HNF1 family motif in super-enhancers was found. We subsequently showed that HNF1A was prominently expressed and significantly upregulated in metastatic cell lines and clinical specimens of liver metastases. Collectively, our study implicates HNF1A as a master transcription factor involved in shaping global super-enhancer landscape in CRC liver metastasis.
2020-11-17 | GSE161558 | GEO
Project description:We interrogated global super-enhancer landscape and sought to discover master regulators governing the liver metastasis of colorectal cancer (CRC). Using de novo analysis, we predicted motif enrichment of master transcription factor in super-enhancers. We show that transcription factor-binding sites of hepatocyte nuclear factor 1 (HNF1) family are enriched at super-enhancers identified in cell lines derived from liver metastases, but not those derived from primary tumors. Using ChIP-Seq of acetylated H3K27, the enrichment of HNF1 binding motifs in super enhancers was found in a cell line derived from xenografted liver metastasis but not the parental cell line. The prediction method was further extended to pancreatic cancer where liver metastasis is also a common finding, and a similar enrichment of HNF1 family motif in super-enhancers was found. We subsequently showed that HNF1A was prominently expressed and significantly upregulated in metastatic cell lines and clinical specimens of liver metastases. Collectively, our study implicates HNF1A as a master transcription factor involved in shaping global super-enhancer landscape in CRC liver metastasis.
2021-10-05 | GSE185331 | GEO
Project description:Super-enhancer landscape shaped by master regulator in liver metastasis of colorectal cancer
| PRJNA768764 | ENA
Project description:Super-enhancer landscape shaped by master regulator in liver metastasis of colorectal cancer [ChIP-seq]
| PRJNA678710 | ENA
Project description:super-ehancer landscape shaped by master regulator in liver metastasis of colorectal cancer [RNA-seq]
| PRJNA768769 | ENA
Project description:Unveiling key oncogenic events in malignancies is the key to improving the prognosis and therapeutic outcome of malignancies. Lines of evidence have shown that super-enhancers control the expression of genes that determine the cell fate, but the oncogenic super-enhancers in colorectal cancer (CRC) and their impact on carcinogens remain largely unexplored. Here, we identified a new oncogenic super-enhancer-regulated gene, IL-20RA, in CRC. Using the integrative analysis of H3K27ac ChIP-seq and RNA-seq in CRC tumors and normal colon tissues, we obtained a series of oncogenic super-enhancers in CRC. We found that super-enhancer inhibition by JQ-1 or iBET-151 suppressed the growth of tumor cells and inhibited the expression of IL-20RA. We found that IL-20RA was highly expressed in the tumor tissue of CRC and related to the advanced stage. Further functional studies showed that knockdown of IL-20RA inhibited the growth and metastasis of CRC. In addition, we found that IL-20RA was involved in regulating oncogenic and immune pathways and affecting the expression of genes related to cell proliferation and immune evasion in CRC. Together, our study demonstrated a novel oncogene in CRC and shed new light on oncogenic super-enhancer contributions to cell proliferation and immune escape.
| S-EPMC8319729 | biostudies-literature
Project description:BackgroundHepatic metastasis is the primary and direct cause of death in individuals with colorectal cancer (CRC) attribute to lack of effective therapeutic targets. The present study aimed to identify potential druggable candidate targets for patients with liver metastatic CRC.MethodsThe transcriptional profiles of super-enhancers (SEs) in primary and liver metastatic CRC were evaluated in publicly accessible CRC datasets. Immunohistochemistry of human CRC tissues was conducted to determine the expression level of CDK12. Cellular proliferation, survival and stemness were examined upon CDK12 inhibition by shCDK12 or a selective CDK12 inhibitor named SR-4835 with multiple in vitro and in vivo assays. RNA sequencing and bioinformatics analyses were carried out to investigate the mechanisms of CDK12 inhibition in CRC cells.ResultsWe identified CDK12 as a driver gene for direct hepatic metastasis in CRC. Suppression of CDK12 led to robust inhibition of proliferation, survival and stemness. Mechanistically, CDK12 intervention preferentially repressed the transcription of SE-associated genes. Integration of the SE landscape and RNA sequencing, BCL2L1 and CCDC137 were identified as SE-associated oncogenic genes to strengthen the abilities of cellular survival, proliferation and stemness, eventually increasing liver metastasis of CRC.ConclusionsOur data highlight the potential of CDK12 and SE-associated oncogenic transcripts as therapeutic targets for patients with liver metastatic CRC.
| S-EPMC9577262 | biostudies-literature
Project description:Despite considerable efforts, the mechanisms linking genomic alterations to the transcriptional identity of cancer cells remain elusive. Integrative genomic analysis, using a network-based approach, identified 407 master regulator (MR) proteins responsible for canalizing the genetics of individual samples from 20 cohorts in The Cancer Genome Atlas (TCGA) into 112 transcriptionally distinct tumor subtypes. MR proteins could be further organized into 24 pan-cancer, master regulator block modules (MRBs), each regulating key cancer hallmarks and predictive of patient outcome in multiple cohorts. Of all somatic alterations detected in each individual sample, >50% were predicted to induce aberrant MR activity, yielding insight into mechanisms linking tumor genetics and transcriptional identity and establishing non-oncogene dependencies. Genetic and pharmacological validation assays confirmed the predicted effect of upstream mutations and MR activity on downstream cellular identity and phenotype. Thus, co-analysis of mutational and gene expression profiles identified elusive subtypes and provided testable hypothesis for mechanisms mediating the effect of genetic alterations.
| S-EPMC8103356 | biostudies-literature
Project description:Widespread aberrant gene expression is a pathological hallmark of polycystic kidney disease (PKD). Numerous pathogenic signaling cascades, including c-Myc, Fos, and Jun, are transactivated. However, the underlying epigenetic regulators are poorly defined. Here we show that H3K27ac, an acetylated modification of DNA packing protein histone H3 that marks active enhancers, is elevated in mouse and human samples of autosomal dominant PKD. Using comparative H3K27ac ChIP-Seq analysis, we mapped over 16000 active intronic and intergenic enhancer elements in Pkd1-mutant mouse kidneys. We found that the cystic kidney epigenetic landscape resembles that of a developing kidney, and over 90% of upregulated genes in Pkd1-mutant kidneys are co-housed with activated enhancers in the same topologically associated domains. Furthermore, we identified an evolutionarily conserved enhancer cluster downstream of the c-Myc gene and super-enhancers flanking both Jun and Fos loci in mouse and human models of autosomal dominant PKD. Deleting these regulatory elements reduced c-Myc, Jun, or Fos abundance and suppressed proliferation and 3D cyst growth of Pkd1-mutant cells. Finally, inhibiting glycolysis and glutaminolysis or activating Ppara in Pkd1-mutant cells lowerd global H3K27ac levels and its abundance on c-Myc enhancers. Thus, our work suggests that epigenetic rewiring mediates the transcriptomic dysregulation in PKD, and the regulatory elements can be targeted to slow cyst growth.
| S-EPMC9841439 | biostudies-literature
Project description: Not available
| S-EPMC10950626 | biostudies-literature