ASCL1 characterizes adrenergic neuroblastoma via its pioneer function and cooperation with core regulatory circuit factors
Lu Wang,
Tze King Tan,
Hyoju Kim,
Dennis Kappei,
Shi Hao Tan,
A. Thomas Look,
Takaomi Sanda
Affiliations
Lu Wang
Cancer Science Institute of Singapore, Singapore 117599, Singapore
Tze King Tan
Cancer Science Institute of Singapore, Singapore 117599, Singapore
Hyoju Kim
Cancer Science Institute of Singapore, Singapore 117599, Singapore
Dennis Kappei
Cancer Science Institute of Singapore, Singapore 117599, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
Shi Hao Tan
Cancer Science Institute of Singapore, Singapore 117599, Singapore
A. Thomas Look
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02216, USA; Division of Pediatric Hematology/Oncology, Boston Children’s Hospital, Boston, MA 02215, USA
Takaomi Sanda
Cancer Science Institute of Singapore, Singapore 117599, Singapore; NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore; Corresponding author
Summary: 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 ADRN genes, accompanied by epigenetic activation and establishment of enhancer-promoter interactions, initiating the ADRN gene expression program. ASCL1 inhibits the transforming growth factor β-SMAD2/3 pathway but activates the bone morphogenetic protein SMAD1-ID3/4 pathway. ASCL1 and other CRC members potentiate each other’s activity, increasing the expression of the original targets and inducing a new set of genes, thereby fully inducing the ADRN program. Our results demonstrate that ASCL1 serves as a pioneer factor and cooperates with CRC factors to characterize the ADRN gene expression program.
