Super-enhancer-associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells [RNA-seq]

Neuroblastoma is a pediatric tumor that accounts for more than 15% of cancer-related deaths in children. Survival chances for high-risk patients are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumors respond to retinoic acid-mediated differentiation. Among neuroblastoma tumors, two phenotypically distinct cell types-adrenergic (ADRN) and mesenchymal (MES), have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries. We hypothesized that distinct super-enhancers in these different tumor cells could mediate differential response to retinoic acid. To this end, we treated four different neuroblastoma cell lines, comprising both ADRN (MYCN amplified and non-amplified) and MES subtypes, with retinoic acid and studied the super-enhancer landscape upon treatment and after removal of retinoic acid. Using H3K27ac ChIP-seq paired with RNA-seq, we compared the super-enhancers in cells that respond to retinoic acid-mediated differentiation versus those that fail to differentiate. We identified unique super-enhancers associated with cells differentiation; however, even among cells that respond to treatment, there was heterogeneity upon removal of retinoic acid, with MYCN amplified cells remaining differentiated whereas MYCN non-amplified cells reverted to a proliferative state. This study identifies regulatory super-enhancers as a plausible mechanism behind the differential response to retinoic acid-mediated differentiation. Overall design: RNA-seq libraries were generated in three neuroblastoma cell lines to investigate the effect of retinoic acid treatment and withdrawal. Three replicates were generated for each condition - control, ATRA treated, and withdrawn.