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

Abstract

The gene transactivation function of nuclear EGFR (nEGFR) has been studied by investigating the genomic co-occupancies of nEGFR and RNA Polymerase II (RNAPII). However, due to RNAPII pausing, the co-recruitment of RNAPII and nEGFR does not necessarily represent productive transactivation. 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.

Nucleocytoplasmic transport of active HER2 causes fractional escape from the DCIS-like state

“…Various roles have been ascribed to nuclear ErbBs 18 . Our results are most concordant with work reporting ErbB-RNA polymerase II co-occupancy along the body of actively transcribed genes 85 such as MIR205HG . Here, ErbBs may directly impact the tyrosyl phosphorylation of RNA polymerase II and its subsequent transcriptional activity 98, 99 .…”

Nuclear EGFR Expression Is Associated With Poor Survival in Laryngeal Carcinoma

“…2,3 In the nucleus, EGFR acts as modulator of DNA replication, DNA repair, and gene transcription. 4 Among diverse nEGFR functions, as a transcription cofactor, it can also interact with and activate the CCND1 gene, a key positive regulator of proliferation. 5 nEGFR has been associated with poor prognosis and worse survival in many cancer types, including breast, ovary, and oropharynx.…”

Nucleocytoplasmic transport of active HER2 causes fractional escape from the DCIS-like state

“…As reported 49,50 , EGFR occupancy often occurred along the gene body of highly expressed genes (TXNIP, NEAT1) and transcription factors of the AP1 (JUNB) and KLF (KLF5) families. The AP-independent loci contained multiple genes previously linked to 3D cell-to-cell heterogeneity in MCF10A-5E cells: KRT5, NFKBIA, and SOD2 20,40,51 .…”