ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry

Lu Wang, Tze King Tan, Adam D. Durbin, Mark W. Zimmerman, Brian J. Abraham, Shi Hao Tan, Phuong Cao Thi Ngoc, Nina Weichert-Leahey, Koshi Akahane, Lee N. Lawton, Jo Lynne Rokita, John M. Maris, Richard A. Young, A. Thomas Look () and Takaomi Sanda ()
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Lu Wang: Cancer Science Institute of Singapore, National University of Singapore
Tze King Tan: Cancer Science Institute of Singapore, National University of Singapore
Adam D. Durbin: Dana-Farber Cancer Institute, Harvard Medical School
Mark W. Zimmerman: Dana-Farber Cancer Institute, Harvard Medical School
Brian J. Abraham: Whitehead Institute for Biomedical Research
Shi Hao Tan: Cancer Science Institute of Singapore, National University of Singapore
Phuong Cao Thi Ngoc: Cancer Science Institute of Singapore, National University of Singapore
Nina Weichert-Leahey: Dana-Farber Cancer Institute, Harvard Medical School
Koshi Akahane: Dana-Farber Cancer Institute, Harvard Medical School
Lee N. Lawton: Whitehead Institute for Biomedical Research
Jo Lynne Rokita: Children’s Hospital of Philadelphia
John M. Maris: Children’s Hospital of Philadelphia
Richard A. Young: Whitehead Institute for Biomedical Research
A. Thomas Look: Dana-Farber Cancer Institute, Harvard Medical School
Takaomi Sanda: Cancer Science Institute of Singapore, National University of Singapore

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract A heritable polymorphism within regulatory sequences of the LMO1 gene is associated with its elevated expression and increased susceptibility to develop neuroblastoma, but the oncogenic pathways downstream of the LMO1 transcriptional co-regulatory protein are unknown. Our ChIP-seq and RNA-seq analyses reveal that a key gene directly regulated by LMO1 and MYCN is ASCL1, which encodes a basic helix-loop-helix transcription factor. Regulatory elements controlling ASCL1 expression are bound by LMO1, MYCN and the transcription factors GATA3, HAND2, PHOX2B, TBX2 and ISL1—all members of the adrenergic (ADRN) neuroblastoma core regulatory circuitry (CRC). ASCL1 is required for neuroblastoma cell growth and arrest of differentiation. ASCL1 and LMO1 directly regulate the expression of CRC genes, indicating that ASCL1 is a member and LMO1 is a coregulator of the ADRN neuroblastoma CRC.

Date: 2019
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DOI: 10.1038/s41467-019-13515-5

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