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. 2022 Mar 11;41:92. doi: 10.1186/s13046-022-02281-w

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© The Author(s) 2022

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

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Fig. 5 — Enhancer/super-enhancer-driven transcription of ADRN CRC genes by MYCN invasion. A Schematic representation of the ADRN CRC composed of a set of super-enhancer (SE)-associated lineage TFs (e.g. PHOX2B, GATA3, HAND2, etc.) invaded by MYCN (red arrows) following MYCN amplification/overexpression. Each TF (ovals) binds its own SE and each of the other SEs belonging to the CRC, thus inducing a powerful feed-forward loop in all the other genes. B Structural drawing of the molecular interactions within the transcriptional unit of a gene belonging to the ADNR CRC (cyan box). The white circle indicates a general TF bound to the promoter site to activate transcription. Starting from the 5′ end, an SE of the ADRN CRC (as indicated in the upper part A) consists of a clustering of E-boxes in close genomic proximity to each other (e.g. three in this figure) bound by all TFs taking part in the ADRN CRC (soft color circles) and invaded by MYCN (red solid circles) when it is amplified/overexpressed. Thanks to the recruitment of the mediator (Med) complex, an SE can interact with the basal transcription machinery and RNA polymerase II (Pol II) at the promoter of the target gene through a looping process to drive its transcription. In addition, overexpressed MYCN can bind a low-affinity E-box or an enhancer of the target gene, thus strongly activating its transcription (thick arrow) and increasing the amount of the gene products (cyan solid circles). The enhancer can be co-occupied by additional TFs together with MYCN (e.g. HAND2 or TWIST1, yellow-orange circles). Invasion of regulatory elements by increased levels of MYCN lead to an enhancer/SE-driven transcription of the target gene. TFs that activate transcription are indicated with “+” within circles. Illustration slightly modified from Perri et al., 2021 [5]