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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE128271 | GEO | 2019/12/17

REPOSITORIES: GEO

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Project description:<p>Non-coding elements in our genomes that play critical roles in complex disease are frequently marked by highly unstable RNA species. Sequencing nascent RNAs attached to an actively transcribing RNA polymerase complex can identify unstable RNAs, including those templated from gene-distal enhancers (eRNAs). However, nascent RNA sequencing techniques remain challenging to apply in some cell lines and especially to intact tissues, limiting broad applications in fields such as cancer genomics and personalized medicine. Here we report the development of chromatin run-on and sequencing (ChRO-seq), a novel run-on technology that maps the location of RNA polymerase using virtually any frozen tissue sample, including samples with degraded RNA that are intractable to conventional RNA-seq. We used ChRO-seq to develop the first maps of nascent transcription in 23 human glioblastoma (GBM) brain tumors and patient derived xenografts. Remarkably, >90,000 distal enhancers discovered using the signature of eRNA biogenesis within primary GBMs closely resemble those found in the normal human brain, and diverge substantially from GBM cell models. Despite extensive overall similarity, 12% of enhancers in each GBM distinguish normal and malignant brain tissue. These enhancers drive regulatory programs similar to the developing nervous system and are enriched for transcription factor binding sites that specify a stem-like cell fate. These results demonstrate that GBMs largely retain the enhancer landscape associated with their tissue of origin, but selectively adopt regulatory programs that are responsible for driving stem-like cell properties. We also identified enhancers and their associated transcription factors that regulate genes characteristic of each known GBM subtype, and discovered a core group of transcription factors that control the expression of genes associated with clinical outcomes. This study uncovers new insights into the molecular etiology of GBM and introduces ChRO-seq which can now be used to map regulatory programs contributing to a variety of complex diseases.</p>

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

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