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The role of the SOX11 lineage-dependency factor as epigenetic master regulator in neuroblastoma

We recently identified SOX11 as an important adrenergic lineage-specific transcription factor in neuroblastoma (NB). Through the induction of factors involved in chromatin landscaping, SOX11 has an epigenetic mediator role in controlling the sympathoblast enhancer landscape.To gain insights into SOX11 dependency, we aim to understand how the normal role of SOX11 during sympathoblast differentiation is co-opted during the process of malignant transformation. Therefore, we will generate a SOX11 compendium of validated direct targets in NB cell lines and explore the dependency role of SOX11 in MYCN-driven NB formation using a novel induced pluripotent stem cell-derived xenograft NB mouse model and MYCN/SOX11 double transgenic-driven zebrafish models. Next, we will generate a genome-wide map of SOX11 binding sites and predicted functionality in normal human adrenergic sympathoblasts and MYCN and/or SOX11-driven in vivo NB models. Integrating these data will give insight into the role of enhanced SOX11 expression on the promoter/enhancer-bound landscape and its predicted functionality in presence or absence of MYCN during tumor formation. In addition, we aim to further establish the SOX11 interactome in NB cells as entry point for novel therapeutic options towards functional inactivation of SOX11. Taken together, we will elucidate the functional co-opted SOX11 epigenetic master regulator role and its interaction with MYCN enhancer invasion in NB formation, opening new therapeutic entry points.




Date:1 Oct 2021 →  Today
Keywords:epigenetics, gene regulation, SOX11
Disciplines:Developmental biology, Computational transcriptomics and epigenomics, Epigenetics, Cancer biology