Nuclear EGFR and Integrator/Super Elongation Complex concurrently binds to Immediate Early Genes for gene transactivation.

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In this study, we integrated gatekeepers of productive transcriptional elongation such as Integrator and Super Elongation Complex (SEC) to interrogate the function of nEGFR. By analyzing publicly available ChIP-seq and RNA-seq data, we aims to 1) explore the function of nEGFR, 2) unravel nEGFR target genes, and 3) discuss potential mechanisms of nEGFR chromatin recruitment. EGF treatment in HeLa cells instigated chromatin recruitment of nEGFR, ERK, RNAPII, Integrator, and SEC in a cluster of 61 EGF-responsive genes. The function of nEGFR was identified as gene-activating rather than gene-repressing. Within the cluster of EGF-responsive genes, nEGFR targeted eleven Immediate Early Genes (IEGs) - JUN, EGR1, JUNB, IER2, KLF2, FOS, FOSL1, RHOB, CCNL1, DUSP2, and DUSP5, which up-regulated >2-fold after EGF stimulation. The promoter of these target genes commonly harbors AT-rich minimal consensus sequences for nEGFR binding. In addition, TCGA data analysis demonstrated positive correlations between EGFR and JUN/FOSL1/RHOB expressions, as well as clinical correlations in specific cancer types. To our knowledge, this is the first study to compare the genome-wide distribution of nEGFR versus Integrator and SEC, providing novel insight into supporting the gene-activating function of nEGFR. We revealed a panel of eleven nEGFR target genes, which concurrently recruited nEGFR, RNAPII, Integrator, and SEC for productive transcriptional elongation.", "claims": [{"id": "claim-method", "statement": "For evaluating the Pearson's correlation coefficient between EGFR and IEG expressions, TCGA RNA-seq data with EGF mRNA expressions above average was subjected to analysis and visualized by ComplexHeatmap package in R. 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Their expressions were significantly associated with overall survival of patients in KM analysis (log-rank p=0.0001-0.0075) and were identified as independent prognostic markers by multivariate Cox regression analysis."}, "evidence": [{"asset": "source:pmid:29290775", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "The function of nEGFR was identified as gene-activating rather than gene-repressing."}, {"asset": "source:pmid:29290775", "locator": "sections[7] \"TCGA RNA-seq and survival data analyses\" paragraph 2", "quote": "TCGA RNA expression data (RNA Seq V2 RSEM) and survival data were queried and downloaded via cBioPortal (http://www.cbioportal.org/), followed by data processing in R environment."}, {"asset": "source:pmid:29290775", "locator": "sections[7] \"TCGA RNA-seq and survival data analyses\" paragraph 2", "quote": "For evaluating the Pearson's correlation coefficient between EGFR and IEG expressions, TCGA RNA-seq data with EGF mRNA expressions above average was subjected to analysis and visualized by ComplexHeatmap package in R. 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RNA-seq and ChIP-seq data shared the same experiment", "ml) for 20 min after 48 hr serum starvation. RNA-seq data was aligned to the human genome hg19 us"], "order_basis": "paper_text_order:587", "id": "assay:2"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["EGFR chromatin recruitment. EGF treatment in HeLa cells instigated chromatin recruitment of nE", "data shared the same experimental condition—HeLa cells were treated with EGF (100 ng/ml) for", "same experimental condition — serum-starved HeLa cells treated with 100 ng/ml EGF for 20 min.", "cells treated with 100 ng/ml EGF for 20 min. 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