Dataset Information

ASCL1: a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

ABSTRACT: Neuroblastoma is an embryonic malignancy originating from early nerve cells. Neuroblastoma retains plasticity, interconverting between the mesenchymal (MES) and adrenergic (ADRN) states, which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, their functional roles and cooperative mechanisms in neuroblastoma pathogenesis are poorly understood. Here, we demonstrate that overexpression of ASCL1 in MES neuroblastoma cells opens closed chromatin at the promoters of key ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, thereby initiating subtype switching. ASCL1 inhibits the TGFb-SMAD2/3 pathway but activates the BMP-SMAD1-ID3/4 pathway, serving as negative feedback to balance the function of ASCL1-TCF12 dimers. ASCL1 and other ADRN CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby promoting conversion to ADRN neuroblastoma. Thus, via its pioneer factor function, ASCL1 serves as a master regulator that characterizes ADRN neuroblastoma.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

DISEASE(S): Neuroblastoma

SUBMITTER: Dennis Kappei

LAB HEAD: Dennis Kappei

PROVIDER: PXD037670 | Pride | 2023-12-08

REPOSITORIES: Pride

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Publications

ASCL1 characterizes adrenergic neuroblastoma via its pioneer function and cooperation with core regulatory circuit factors.

Wang Lu L Tan Tze King TK Kim Hyoju H Kappei Dennis D Tan Shi Hao SH Look A Thomas AT Sanda Takaomi T

Cell reports 20231205 12

Neuroblastoma originates from developing neural crest and can interconvert between the mesenchymal (MES) and adrenergic (ADRN) states, each of which are controlled by different sets of transcription factors forming the core regulatory circuit (CRC). However, the roles of CRC factors in induction and maintenance of specific state are poorly understood. Here, we demonstrate that overexpression of ASCL1, an ADRN CRC factor, in MES neuroblastoma cells opens closed chromatin at the promoters of key A ...[more]

PMID: 38060444

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Dataset Information

ASCL1: a pioneer factor that induces subtype switching and characterizes adrenergic neuroblastoma

Publications

ASCL1 characterizes adrenergic neuroblastoma via its pioneer function and cooperation with core regulatory circuit factors.

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