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Series GSE80153 Query DataSets for GSE80153
Status Public on Jan 30, 2018
Title Enhancer invasion shapes MYCN dependent transcriptional amplification in neuroblastoma [RNA-seq]
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary In neuroblastoma, amplification of the oncogenic basic helix-loop-helix (bHLH) transcription factor (TF) MYCN is the defining prognosticator of high-risk disease, occurs in one-third of neuroblastoma, and drastically reduces overall survival rates1,2. As a proto-oncogene, targeted MYCN overexpression in peripheral neural crest is sufficient to initiate disease in mouse models3. In MYCN amplified neuroblastoma, elevated expression of the factor is crucial to maintain tumor stemness4,5 and is associated with increased proliferation and aberrant cell cycle progression, as these tumors lack the ability to arrest in G1 in response to irradiation6-9. MYCN down-regulation broadly reverses these oncogenic phenotypes in a variety of neuroblastoma models10-12 and recent thereapeutic strategies to indirectly target MYCN production or protein stability have reduced tumor growth in vivo13-15. These observations motivate an investigation of MYCN binding in MYCN amplified tumors as it remains fundamentally unclear how elevated levels of the factor occupy the genome and alter transcriptional programs in neuroblastoma. Here we present the first dynamic chromatin and transcriptional landscape of direct MYCN perturbation in neuroblastoma. We find that at oncogenic levels, MYCN associates with E-box (CANNTG) binding motifs in an affinity dependent manner across most active cis-regulatory promoters and enhancers. MYCN shutdown globally reduces histone acetylation and transcription, consistent with prior descriptions of MYC proteins as non-linear amplifiers of gene expression. We establish that MYCN load at the promoter and proximal enhancers predicts transcriptional responsiveness to MYCN shutdown and that MYCN enhancer binding occurs prominently at the most strongly occupied and down-regulated genes, suggesting a role for these tissue specific elements in predicating MYCN responsive “target” genes. At these invaded enhancers, we identify the lineage specific bHLH TWIST1 as a key collaborator and dependency of oncogenic MYCN. These data suggest that MYCN enhancer invasion helps shape transcriptional amplification of the neuroblastoma gene expression program to promote tumorigenesis.
Overall design RNA-Seq in SHEP-21 DOX treated time course. RNA-Seq in BE2C cells
Contributor(s) Zeid R, Bradner JE, Lin CY
Citation(s) 29379199
Submission date Apr 11, 2016
Last update date May 15, 2019
Contact name James Bradner
Organization name Dana-Farber Cancer Institute
Department Medical Oncology
Lab Bradner Lab
Street address 450 Brookline
City Boston
State/province MA
ZIP/Postal code 02215
Country USA
Platforms (1)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (49)
GSM2113549 SHEP21_0HR_RNA-seq_rep2
GSM2113550 SHEP21_0HR_RNA-seq_rep3
GSM2113551 SHEP21_16HR_RNA-seq_rep1
This SubSeries is part of SuperSeries:
GSE80154 Enhancer invasion shapes MYCN dependent transcriptional amplification in neuroblastoma
BioProject PRJNA318042
SRA SRP073112

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SOFT formatted family file(s) SOFTHelp
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE80153_BE2C_TWIST_all_fpkm_exprs_norm.txt.gz 2.8 Mb (ftp)(http) TXT
GSE80153_BE2C_TWIST_all_fpkm_exprs_raw.txt.gz 1.1 Mb (ftp)(http) TXT
GSE80153_SHEP21_all_fpkm_exprs_norm.txt.gz 3.2 Mb (ftp)(http) TXT
GSE80153_SHEP21_all_fpkm_exprs_raw.txt.gz 1.3 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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