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Widespread perturbation of ETS factor binding sites in cancer [CASCADE_HOOK_SIGGERS_v3]

ABSTRACT: Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.

ORGANISM(S): Homo sapiens

PROVIDER: GSE222435 | GEO | 2023/01/09

REPOSITORIES: GEO

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Widespread perturbation of ETS factor binding sites in cancer [SCREEN_HOOK_SIGGERS_v2]

Project description:Although >90% of somatic mutations reside in non-coding regions, few have been reported as cancer drivers. To predict driver non-coding variants (NCVs), we present a novel transcription factor (TF)-aware burden test (TFA-BT) based on a model of coherent TF function in promoters. We applied our TFA-BT to NCVs from the Pan-Cancer Analysis of Whole Genomes cohort and predicted 2,555 driver NCVs in the promoters of 813 genes across 20 cancer-types. These genes are enriched in cancer-related gene ontologies, essential genes, and genes associated with cancer prognosis. We found that 765 candidate driver NCVs alter transcriptional activity, 510 lead to differential binding of TF-cofactor regulatory complexes, and that they primarily impact the binding of ETS factors. Finally, we show that different NCVs within a promoter often affect transcriptional activity through shared mechanisms. Our integrated computational and experimental approach shows that cancer NCVs are widespread and that ETS factors are commonly disrupted.

2023-01-09 | GSE222434 | GEO

Widespread perturbation of ETS factor binding sites in cancer

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A functional liaison between E2F and the aberrant ETS oncogene EWS/FLI1 in Ewing's sarcoma

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Genetic dependencies associated with transcription factor activities in human cancer cell lines [CROP-seq]

Project description:Transcription factors (TFs) are important mediators of aberrant transcriptional programs in cancer cells. In this study, we focused on TF activity (TFa) as a new biomarker for cell line-selective anti-proliferative effects, in that high TFa predicts sensitivity to loss-of-function of a given gene (i.e., genetic dependencies (GD)). Our linear regression-based framework identified 3,047 pan-cancer and 3,952 cancer-typespecific candidate TFa-GD associations from cell line data, which were then crossexamined for impact on survival in patient cohorts. One of the most prominent biomarkers was TEAD1 activity, whose associations with its predicted GDs were validated through experimental evidence as proof of concept. Overall, these TFa-GD associations represent an attractive resource for identifying innovative, biomarkerdriven hypotheses for drug discovery programs in oncology.

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Genetic dependencies associated with transcription factor activities in human cancer cell lines [SLAM-seq]

Project description:Transcription factors (TFs) are important mediators of aberrant transcriptional programs in cancer cells. In this study, we focused on TF activity (TFa) as a new biomarker for cell line-selective anti-proliferative effects, in that high TFa predicts sensitivity to loss-of-function of a given gene (i.e., genetic dependencies (GD)). Our linear regression-based framework identified 3,043 pan-cancer and 3,952 cancer-type-specific candidate TFa-GD associations from cell line data, which were then cross-examined for impact on survival in patient data. One of the most prominent biomarkers was TEAD1 activity, whose associations with its predicted GDs were validated through experimental evidence as proof of concept. Overall, these TFa-GD pairs represent an attractive resource for identifying innovative, biomarker-driven hypotheses for drug discovery programs in oncology.

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A functional liaison between E2F and the aberrant ETS oncogene EWS/FLI1 in Ewing's sarcoma

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Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers

Project description:Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations are commonly believed to be due to locally inhibited DNA repair. Here, we first show that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit strong increases in CPD formation efficacy in a manner consistent with tumor mutation data at the single-base level. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory elements including ETS sites, our data supports that elevated DNA damage formation at specific genomic bases is at the core of the prominent promoter mutation hotspots seen in skin cancers, thus explaining a key phenomenon in whole-genome cancer analyses.

2018-12-03 | GSE119249 | GEO

The p30 isoform of CEBPA uncovers a silent enhancer to drive the expression of the tumor promoting factor CD73 in CEBPA mutant AML

Project description:The key myeloid transcription factor (TF) CEBPA is frequently mutated in acute myeloid leukemia (AML), but the molecular ramifications of this leukemic driver mutation remain elusive. To investigate CEBPA mutant AML, we compared gene expression changes in human CEBPA mutant AML and in the corresponding CebpaLp30 mouse model, and identified a conserved cross-species transcriptional program. ChIP-seq revealed aberrantly activated enhancers, exclusively occupied by the leukemia-associated CEBPA-p30 isoform. One leukemic-enhancer upstream of Nt5e, encoding CD73, was physically and functionally linked to this conserved AML gene, and could be activated by CEBPA. Targeting of CD73-adenosine signaling increased AML survival in transplanted mice. Our data indicate a first-in-class link between a TF cancer driver mutation and a druggable, direct transcriptional target.

2019-08-08 | PXD011359 | Pride

Control of cell identity and early neural fate commitment by the enhancer module of Integrator

Project description:Lineage-specific transcription factors (TFs) operate as master orchestrators of developmental processes by activating select cis-regulatory enhancers and proximal promoters. Direct DNA binding of TFs ultimately drives context-specific recruitment of the basal transcriptional machinery that comprises RNA Polymerase II (RNAPII) and a host of polymerase-associated multiprotein complexes, including the metazoan-specific Integrator complex. Integrator is primarily known to modulate RNAPII processivity and to surveil RNA integrity across coding genes. Here we show an enhancer module of Integrator that directs cell fate specification by promoting epigenetic changes and TF binding at neural enhancers. Depletion of Integrator’s INTS10 upends neural traits and derails cells towards mesenchymal identity. Commissioning of neural enhancers relies on Integrator’s enhancer module, which stabilizes SOX2 binding at chromatin upon exit from pluripotency. We propose Integrator as a functional bridge between enhancers and promoters and a main driver of early development, providing new insight into a growing family of neurodevelopmental syndromes.

2024-08-15 | PXD054928 | Pride

RNAi profiling by array of human Ewings carcinoma cells to down regulate EWS-FLI1

Project description:We report here the DNA-binding profiles for all human and mouse ETS factors, which we generated using two different methods: a high-throughput microwell-based transcription factor DNA-binding specificity assay, and protein binding microarrays (PBMs). Both approaches reveal that the ETS binding profiles cluster into four distinct classes, and that all ETS factors linked to cancer, ERG, ETV1, ETV4 and FLI1, fall into just one of these classes. We identify amino acid residues that are critical for the differences in specificity between all the classes, and confirm the specificities in vivo using chromatin immunoprecipitation followed by sequencing (ChIP-seq) for a member of each class. To determine whether the ChIP-seq peaks were near genes regulated by the respective ETS-factors, we used RNAi to downregulate EWS-FLI1 in SK-N-MC Ewing's sarcoma cells. The results indicate that even relatively small differences in in vitro binding specificity of a TF contribute to site selectivity in vivo.

2010-07-07 | E-MEXP-2759 | biostudies-arrayexpress

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