SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

Decaesteker, B.; Louwagie, A.; Loontiens, S.; De Vloed, F.; Roels, J.; Vanhauwaert, S.; De Brouwer, S.; Sanders, E.; Denecker, G.; D'haene, E.; Van Haver, S.; Van Loocke, W.; Van Dorpe, J.; Creytens, D.; Van Roy, N.; Pieters, T.; Van Neste, C.; Fischer, M.; Van Vlierberghe, P.; Roberts, S. S.; Schulte, J.; Ek, S.; Versteeg, R.; Koster, J.; van Nes, J.; De Preter, K.; Speleman, F.

doi:10.1101/2020.08.21.261131

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bioRxiv · 10.1101/2020.08.21.261131

SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma

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Abstract

The pediatric extra-cranial tumor neuroblastoma (NB) is characterised by a low mutation burden while copy number alterations are present in most high-risk cases. We identified SOX11 as a strong lineage dependency transcription factor in adrenergic NB based on recurrent chromosome 2p focal gains and amplifications, its specific expression in the normal sympatho-adrenal lineage and adrenergic NBs and its regulation by multiple adrenergic specific cis-interacting (super-)enhancers. Adrenergic NBs are strongly dependent on high SOX11 expression levels for growth and proliferation. Through genome-wide DNA-binding and transcriptome analysis, we identified and validated functional SOX11 target genes, several of which implicated in chromatin remodeling and epigenetic modification. SOX11 controls chromatin accessibility predominantly affecting distal adrenergic lineage-specific enhancers marked by binding sites of the adrenergic core regulatory circuitry. During normal sympathoblast differentiation we find expression of SOX11 prior to members of the adrenergic core regulatory circuitry. Given the broad control of SOX11 of multiple epigenetic regulatory complexes and its presumed pioneer factor function, we propose that adrenergic NB cells have co-opted the normal role of SOX11 as a crucial regulator of chromatin accessibility and cell identity.

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Decaesteker, B., Louwagie, A., Loontiens, S., De Vloed, F., Roels, J., Vanhauwaert, S., De Brouwer, S., Sanders, E., Denecker, G., D'haene, E., Van Haver, S., Van Loocke, W., Van Dorpe, J., Creytens, D., Van Roy, N., Pieters, T., Van Neste, C., Fischer, M., Van Vlierberghe, P., Roberts, S. S., Schulte, J., Ek, S., Versteeg, R., Koster, J., van Nes, J., De Preter, K., Speleman, F.. 2020-08-21. SOX11 is a lineage-dependency factor and master epigenetic regulator in neuroblastoma. https://doi.org/10.1101/2020.08.21.261131

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