Retinoic acid rewires the adrenergic core regulatory circuitry of childhood neuroblastoma.

Abstract

Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with <i>MYCN</i> 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 <i>MYCN</i>-amplified neuroblastoma cells are treated with retinoic acid, histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of <i>PHOX2B</i> and <i>GATA3</i>, together with the activation of new super-enhancers that drive high levels of <i>MEIS1</i> and <i>SOX4</i> expression. These findings indicate that treatment with retinoids can reprogram the enhancer landscape, resulting in down-regulation of <i>MYCN</i> 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 <i>MYCN</i> despite massive levels of amplification of this gene.