Super-enhancer associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells

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Gomez, Roshna Lawrence 
Woods, Laura M 
Ramachandran, Revathy 
Abou Tayoun, Ahmad N 
Philpott, Anna 

jats:pNeuroblastoma is a pediatric tumour that accounts for more than 15% of cancer-related deaths in children. High-risk tumours are often difficult to treat, and patients’ survival chances are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumours differentiate in response to retinoic acid. Within neuroblastoma tumors, two phenotypically distinct cell types have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries: adrenergic (ADRN) and mesenchymal (MES). We hypothesized that the distinct super-enhancers in these different tumour cells mediate differential response to retinoic acid. To this end, three different neuroblastoma cell lines, ADRN (jats:italicMYCN</jats:italic> amplified and non-amplified) and MES cells, were treated with retinoic acid, and changes in the super-enhancer landscape upon treatment and after subsequent removal of retinoic acid was studied. Using ChIP-seq for the active histone mark H3K27ac, paired with RNA-seq, we compared the super-enhancer landscape in cells that undergo neuronal differentiation in response to retinoic acid versus those that fail to differentiate and identified unique super-enhancers associated with neuronal differentiation. Among the ADRN cells that respond to treatment, jats:italicMYCN</jats:italic>-amplified cells remain differentiated upon removal of retinoic acid, whereas jats:italicMYCN</jats:italic> non-amplified cells revert to an undifferentiated state, allowing for the identification of super-enhancers responsible for maintaining differentiation. This study identifies key super-enhancers that are crucial for retinoic acid-mediated differentiation.</jats:p>


Peer reviewed: True

Acknowledgements: We gratefully thank Prof. Deborah Tweddle for providing the neuroblastoma cell lines. We thank Prof. Jason Carroll, and Shakhzada Ibragimova for helpful discussions. Finally, we thank Divinn Lal, Dr. Sathishkumar Ramaswamy, and Maha ELNaofal from Al Jalila Genomics Center for their help. We would like to acknowledge the support of the Mohammed Bin Rashid University of Medicine and Health Sciences and Al Jalila Foundation.

Cell and Developmental Biology, neuroblastoma, super-enhancers, retinoic acid, differentiation, treatment-resistance
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Frontiers in Cell and Developmental Biology
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Frontiers Media SA