Retinoic acid rewires the adrenergic core regulatory circuitry of childhood neuroblastoma

Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with to drive the oncogenic gene expression program. For neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation. Here,...

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Bibliographic Details
Published in:Science advances 2021-10, Vol.7 (43), p.eabe0834-eabe0834
Main Authors: Zimmerman, Mark W, Durbin, Adam D, He, Shuning, Oppel, Felix, Shi, Hui, Tao, Ting, Li, Zhaodong, Berezovskaya, Alla, Liu, Yu, Zhang, Jinghui, Young, Richard A, Abraham, Brian J, Look, A Thomas
Format: Article
Language:English
Subjects:
Biomedicine and Life Sciences
Cancer
Genetics
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Summary:Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with to drive the oncogenic gene expression program. For neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation. Here, we show that when -amplified neuroblastoma cells are treated with retinoic acid, histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of and , together with the activation of new super-enhancers that drive high levels of and expression. These findings indicate that treatment with retinoids can reprogram the enhancer landscape, resulting in down-regulation of expression, while establishing a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids in high-risk neuroblastoma and explain the rapid down-regulation of expression of despite massive levels of amplification of this gene.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abe0834