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Intron 1-Mediated Regulation Of EGFR Expression In EGFR-Dependent Malignancies

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128275 | GEO | 2019/12/17

REPOSITORIES: GEO

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Intron 1-Mediated Regulation Of EGFR Expression In EGFR-Dependent Malignancies [ChIP-Seq]

Project description:Here, we performed ChIP-seq and ATAC-seq and identified two novel super enhancers (SE1 and SE2) responsible for EGFR transcription present within the first intron of the EGFR gene in HNSCC and GBM. SE1 and SE2 span 37kb and 33kb respectively, contain H3K27Ac enhancer histone marks and open chromatin, functionally enhance transcription in reporter assays, interact with the EGFR promoter, and negatively impact EGFR transcript levels and anchorage-independent growth when perturbed by CRISPR/Cas9-deletion and dCas9-KRAB-silencing. We utilize in silico methods to identify AP-1 family transcription factors as critical for EGFR enhancers in HNSCC and GBM, and confirm their role through ChIP-qPCR and a dominant-negative c-Jun. Our results identify and characterize these novel enhancers, shedding light on the role that epigenetic mechanisms play in regulating EGFR transcription in EGFR-dependent cancer types and presents a novel angle by which these malignancies can be treated.

2019-12-17 | GSE128272 | GEO

Intron 1-Mediated Regulation Of EGFR Expression In EGFR-Dependent Malignancies [ATAC-Seq]

2019-12-17 | GSE128271 | GEO

Intron 1-Mediated Regulation of <i>EGFR</i> Expression in EGFR-Dependent Malignancies Is Mediated by AP-1 and BET Proteins.

Project description:The epidermal growth factor receptor (EGFR) is overexpressed in numerous solid tumors and is the subject of extensive therapeutic efforts. Much of the research on EGFR is focused on protein dynamics and downstream signaling; however, few studies have explored its transcriptional regulation. Here, we identified two enhancers (CE1 and CE2) present within the first intron of the EGFR gene in models of glioblastoma (GBM) and head and neck squamous cell carcinoma (HNSCC). CE1 and CE2 contain open chromatin and H3K27Ac histone marks, enhance transcription in reporter assays, and interact with the EGFR promoter. Enhancer genetic deletion by CRISPR/Cas9 significantly reduces EGFR transcript levels, with double deletion exercising an additive effect. Targeted repression of CE1 and CE2 by dCas9-KRAB demonstrates repression of transcription similar to that of genomic deletion. We identify AP-1 transcription factor family members in concert with BET bromodomain proteins as modulators of CE1 and CE2 activity in HNSCC and GBM through de novo motif identification and validate their presence. Genetic inhibition of AP-1 or pharmacologic disruption of BET/AP-1 binding results in downregulated EGFR protein and transcript levels, confirming a role for these factors in CE1 and CE2. Our results identify and characterize these novel enhancers, shedding light on the role that epigenetic mechanisms play in regulating EGFR transcription in EGFR-dependent cancers. IMPLICATIONS: We identify critical constituent enhancers present in the first intron of the EGFR gene, and provide a rationale for therapeutic targeting of EGFR intron 1 enhancers through perturbation of AP-1 and BET in EGFR-positive malignancies.

| S-EPMC6825583 | biostudies-literature

Intron 1-Mediated Regulation Of EGFR Expression In EGFR-Dependent Malignancies

Project description:Intron 1-Mediated Regulation Of EGFR Expression In EGFR-Dependent Malignancies

| PRJNA526925 | ENA

Topoisomerase I cleavage complexes preferentially down-regulate ubiquitin- and RNA degradation-related transcripts in relationship to gene length, exon-intron junctions and p53-dependent up-regulation of miR-142-3p

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-04-17 | E-GEOD-37358 | biostudies-arrayexpress

Orchestrated intron retention regulates normal granulocyte differentiation

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2013-06-27 | E-GEOD-48307 | biostudies-arrayexpress

CTCF/CP190 and ISWI dependent regulation of nucleosome occupancy

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2014-08-11 | E-GEOD-51600 | biostudies-arrayexpress

Intron 1-Mediated Regulation Of EGFR Expression In EGFR-Dependent Malignancies [ATAC-Seq]

Project description:Intron 1-Mediated Regulation Of EGFR Expression In EGFR-Dependent Malignancies [ATAC-Seq]

| PRJNA526926 | ENA

Intron 1-Mediated Regulation Of EGFR Expression In EGFR-Dependent Malignancies [ChIP-Seq]

Project description:Intron 1-Mediated Regulation Of EGFR Expression In EGFR-Dependent Malignancies [ChIP-Seq]

| PRJNA526927 | ENA

Genome-wide MAF1-dependent regulation of RNA polymerase III transcription

Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

2016-02-15 | E-GEOD-73936 | biostudies-arrayexpress

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