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GEO help: Mouse over screen elements for information. |
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| 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
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| 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.
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| Overall design |
ChIP-Seq for H3K27ac and GATA3 in neuroblastoma cell lines
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| 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 |
| E-mail(s) |
young_computation@wi.mit.edu
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| Phone |
617-258-5219
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| Organization name |
Whitehead Institute for Biomedical Research
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| Lab |
Young Lab
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| Street address |
9 Cambridge Center
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| City |
Cambridge |
| State/province |
MA |
| ZIP/Postal code |
02142 |
| Country |
USA |
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| Platforms (1) |
| GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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| Samples (14)
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| GSM1602668 |
ChIP: GATA3_sc-22206X_Be2c_103014 |
| GSM1602669 |
Input for ChIP:SHSY5Y_103014 |
| GSM1602670 |
Input for ChIP:Be2c_103014 |
| GSM1680101 |
ChIP: H3K27ac_ab4729_BE2_012615 [lab: Look-DFCI] |
| GSM1680102 |
ChIP: GATA3_sc-22206X_BE2_012615 [lab: Look-DFCI] |
| GSM1680103 |
ChIP: Input_BE2_012615 [lab: Look-DFCI] |
| GSM1680104 |
ChIP: H3K27ac_ab4729_NGP_012615 [lab: Look-DFCI] |
| GSM1680105 |
ChIP: GATA3_sc-22206X_NGP_012615 [lab: Look-DFCI] |
| GSM1680106 |
ChIP: Input_NGP_012615 [lab: Look-DFCI] |
| GSM1680107 |
ChIP: H3K27ac_ab4729_BE2C _012615 [lab: Look-DFCI] |
| GSM1680108 |
ChIP: Input_BE2C_012615 [lab: Look-DFCI] |
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| Relations |
| BioProject |
PRJNA274662 |
| SRA |
SRP053234 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE65664_RAW.tar |
1.1 Gb |
(http)(custom) |
TAR (of WIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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