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Retinoic acid rewires the adrenergic core regulatory circuitry of neuroblastoma but can be subverted by enhancer hijacking of MYC or MYCN

By Mark W. Zimmerman, Adam D. Durbin, Shuning He, Felix Oppel, Hui Shi, Ting Tao, Zhaodong Li, Alla Berezovskaya, Yu Liu, Jinghui Zhang, Richard A. Young, Brian J. Abraham, A. Thomas Look

Posted 24 Jul 2020
bioRxiv DOI: 10.1101/2020.07.23.218834

Neuroblastoma cell identity depends on a core regulatory circuit (CRC) of transcription factors that collaborate with MYCN to drive the oncogenic gene expression program. For neuroblastomas dependent on the adrenergic CRC, treatment with retinoids can inhibit cell growth and induce differentiation in both primary neuroblastomas and cell lines; however, the underlying mechanisms remain unclear. Here we show that when MYCN-amplified neuroblastomas cells are treated with all-trans retinoic acid (ATRA), histone H3K27 acetylation and methylation become redistributed to decommission super-enhancers driving the expression of PHOX2B and GATA3, together with the activation of new super-enhancers that drive high levels of MEIS1, HIC1 and SOX4 expression. These findings indicate that treatment with ATRA can reprogram the enhancer landscape to collapse the adrenergic CRC, resulting in downregulation of MYCN expression, while upregulating a new retino-sympathetic CRC that causes proliferative arrest and sympathetic differentiation. Thus, we provide mechanisms that account for the beneficial effects of retinoids against high-risk neuroblastoma and explain the rapid downregulation of expression of MYCN despite massive levels of gene amplification. ### Competing Interest Statement B.J.A. is a shareholder in Syros Pharmaceuticals. R.A.Y. is a shareholder in Syros Pharmaceuticals and is a consultant/advisory board member for the same. The other authors declare no competing interests.

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