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

Author

Listed:
  • Lu Wang

    (Cancer Science Institute of Singapore, National University 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
    Boston Children’s Hospital
    The Broad Institute of MIT and Harvard)

  • Mark W. Zimmerman

    (Dana-Farber Cancer Institute, Harvard Medical School)

  • Brian J. Abraham

    (Whitehead Institute for Biomedical Research
    St. Jude Children’s Research Hospital)

  • 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
    Boston Children’s Hospital)

  • Koshi Akahane

    (Dana-Farber Cancer Institute, Harvard Medical School
    University of Yamanashi)

  • Lee N. Lawton

    (Whitehead Institute for Biomedical Research)

  • Jo Lynne Rokita

    (Children’s Hospital of Philadelphia
    Children’s Hospital of Philadelphia)

  • John M. Maris

    (Children’s Hospital of Philadelphia
    University of Pennsylvania)

  • Richard A. Young

    (Whitehead Institute for Biomedical Research
    Biology Department, MIT)

  • A. Thomas Look

    (Dana-Farber Cancer Institute, Harvard Medical School
    Boston Children’s Hospital)

  • Takaomi Sanda

    (Cancer Science Institute of Singapore, National University of Singapore
    National University of Singapore)

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.

Suggested Citation

  • 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. Ma, 2019. "ASCL1 is a MYCN- and LMO1-dependent member of the adrenergic neuroblastoma core regulatory circuitry," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13515-5
    DOI: 10.1038/s41467-019-13515-5
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    Cited by:

    1. Cécile Thirant & Agathe Peltier & Simon Durand & Amira Kramdi & Caroline Louis-Brennetot & Cécile Pierre-Eugène & Margot Gautier & Ana Costa & Amandine Grelier & Sakina Zaïdi & Nadège Gruel & Irène Ji, 2023. "Reversible transitions between noradrenergic and mesenchymal tumor identities define cell plasticity in neuroblastoma," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Hsiao-Yun Chen & Yavuz T. Durmaz & Yixiang Li & Amin H. Sabet & Amir Vajdi & Thomas Denize & Emily Walton & Yasmin Nabil Laimon & John G. Doench & Navin R. Mahadevan & Julie-Aurore Losman & David A. B, 2022. "Regulation of neuroendocrine plasticity by the RNA-binding protein ZFP36L1," Nature Communications, Nature, vol. 13(1), pages 1-22, December.

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