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

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

PROVIDER: PRJNA526927 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8723830.fastq.gz	Fastqsanger.gz
	SRR8723840.fastq.gz	Fastqsanger.gz
	SRR8723831.fastq.gz	Fastqsanger.gz
	SRR8723841.fastq.gz	Fastqsanger.gz
	SRR8723832.fastq.gz	Fastqsanger.gz

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Similar Datasets

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

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: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 EGFR Expression In EGFR-Dependent Malignancies

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-12-17 | GSE128275 | 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

SYK activity modulates the EGFR-dependent transcriptome

Project description:SYK activity modulates the EGFR-dependent transcriptome

| PRJNA417718 | ENA

SYK activity modulates the EGFR-dependent transcriptome

Project description:Background: Among all gynecologic malignancies, epithelial ovarian cancer has the highest case-to-fatality ratio. Most patients are diagnosed at advanced stages and recurrence is common and accounts for disease-related mortality. Spleen tyrosine kinase (SYK) is an emerging cancer-associated kinase upregulated in recurrent tumors and is amenable for inhibition using small compounds that have been studied in clinical trials for autoimmune diseases. Our previous proteomic analysis identified several novel SYK substrates including EGFR and ERBB2. Here, we investigated the cross-talk between these pathways in ovarian carcinomas. Methods: Immunohistochemistry and immunoblotting were utilized to assess SYK and EGFR phosphorylation in ovarian serous carcinomas. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. To study its role in EGFR signaling, SYK activity was modulated using a small molecule inhibitor, a syngeneic knockout, and an active kinase inducible system. We applied RNA-seq to investigate the SYK-regulated EGF-induced transcriptome. Results: Intense immunoreactivity of active pSYK(Y525/526) correlated with poor overall survival in two independent ovarian cancer cohorts. SYK directly phosphorylated EGFR and ERBB2, while knockout of SYK reduces their phosphorylation. Phosphorylation levels of SYK(Y525/526) positively correlated with EGFR(Y1187) and STAT3(Y705). Active SYK reduced sensitivity to the EGFR/ERBB2 inhibitor, lapatinib, and SYK non-phosphorylatable EGFR mutant was more sensitive to paclitaxel. SYK modulated the EGF-induced transcriptome, supporting its involvement in EGFR/ERBB2-regulated transcriptional activity. Conclusions: Our findings suggest an upstream role of SYK in regulating the EGFR/ERBB2 signaling, and provide a biological rationale for targeting SYK in ovarian cancer therapy.

2020-11-08 | GSE106716 | GEO

Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

Project description:EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported however the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer.

2018-08-31 | GSE115864 | GEO

Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

Project description:Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

| PRJNA476332 | ENA