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Series GSE65664 Query DataSets for GSE65664
Status Public on Oct 18, 2015
Title Genetic predisposition to neuroblastoma mediated by a single nucleotide polymorphism within a LMO1 oncogene super-enhancer element
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility in children and oncogenic addiction to LMO1 in the tumor cells1. Here we sought to discover the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation, and transcription factor binding sites. SNP rs2168101 G>T was the most highly associated variant (combined P=7.47x10-29, Odds Ratio 0.65, 95% CI: 0.60-0.70) and resided in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumor formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P=0.028) in neuroblastoma primary tumors and ablates GATA3 binding (P=0.007). We demonstrate monoallelic LMO1 expression from the G-containing strand in tumors heterozygous for this SNP as demonstrated both by RNA sequencing (P<0.0001) and reporter assays (P=0.002). These findings show that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumor cells.
Overall design ChIP-Seq for H3K27ac and GATA3 in neuroblastoma cell lines
Contributor(s) Wood AC, Oldridge D, Crimmins I, Sussman R, Winter C, McDaniel LD, Zhu S, Weichert N, Durbin AD, Abraham BJ, Anders L, Tian L, Wei JS, Khan J, Bramlett K, Rahman N, Capasso M, Young RA, Hakonarson H, Diskin SJ, Look AT, Maris JM
Citation(s) 26560027
Submission date Feb 05, 2015
Last update date May 15, 2019
Contact name Richard A Young
Phone 617-258-5219
Organization name Whitehead Institute for Biomedical Research
Lab Young Lab
Street address 9 Cambridge Center
City Cambridge
State/province MA
ZIP/Postal code 02142
Country USA
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (14)
GSM1602665 ChIP: H3K27ac_ab4729_SHSY5Y_103014
GSM1602666 ChIP: GATA3_sc-22206X_Kelly_103014
GSM1602667 ChIP: GATA3_sc-22206X_SHSY5Y_103014
BioProject PRJNA274662
SRA SRP053234

Download family Format
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Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE65664_RAW.tar 1.1 Gb (http)(custom) TAR (of WIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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