A polymorphism in the LMO1 super-enhancer protects against neuroblastoma.
Major finding: A polymorphism in the LMO1 super-enhancer protects against neuroblastoma.
Mechanism: The rs2168101 SNP reduces GATA3 binding to the LMO1 super-enhancer, repressing LMO1 expression.
Impact: Super-enhancer–mediated LMO1 expression may be clinically exploitable for neuroblastoma treatment.
LIM domain only 1 (LMO1) is a neuroblastoma oncogene that has been identified as a disease susceptibility locus in neuroblastoma genome-wide association studies. However, the causal DNA sequence variation that underlies the association of LMO1 with neuroblastoma tumorigenesis has not been defined. Using fine-mapping of germline LMO1 SNPs, Oldridge, Wood, and colleagues identified a protective single-nucleotide polymorphism (SNP), rs2168101 G>T, as the most significantly associated SNP within the LMO1 locus. This association was confirmed in additional European neuroblastoma cohorts; however, the rs2168101 SNP is rare or absent in African populations, suggesting that it is a newly evolved polymorphism and may partially explain why high-risk neuroblastoma is more prevalent in African-Americans. The SNP is located in a highly conserved active super-enhancer region as determined by DNase I sensitivity, p300 binding, and acetylation of histone H3 lysine 27, and mRNA sequencing of high-risk neuroblastoma tumors showed that LMO1 was more highly expressed in G/G homozygous tumors compared with G/T tumors. Allelic imbalance was detected in rs2168101 heterozygous G/T neuroblastoma cell lines, with the G risk allele expressed more highly than the protective T allele. No T/T genotype tumors were observed in the high-risk neuroblastoma mRNA-sequencing cohort, further supporting its protective effect, whereas the G/G genotype was associated with decreased event-free survival in patients with neuroblastoma compared with the G/T and T/T genotypes. The rs2168101 SNP resides in a conserved GATA-binding motif, and chromatin-immunoprecipitation sequencing indicated that the SNP-associated T allele reduced binding of the GATA3 transcription factor to the LMO1 locus. In G allele—expressing cell lines harboring the intact GATA motif, GATA3 knockdown decreased LMO1 expression and reduced cell growth, suggesting that GATA3 is important in regulating LMO1 expression in neuroblastoma. These findings provide a mechanism to explain the genetic association between the LMO1 SNP rs2168101 and neuroblastoma risk through disruption of GATA transcription factor binding in the LMO1 super-enhancer.
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