Lineage specific transcription factor waves reprogram neuroblastoma from self-renewal to differentiation

Nat Commun. 2024 Apr 23;15(1):3432. doi: 10.1038/s41467-024-47166-y.


Temporal regulation of super-enhancer (SE) driven transcription factors (TFs) underlies normal developmental programs. Neuroblastoma (NB) arises from an inability of sympathoadrenal progenitors to exit a self-renewal program and terminally differentiate. To identify SEs driving TF regulators, we use all-trans retinoic acid (ATRA) to induce NB growth arrest and differentiation. Time-course H3K27ac ChIP-seq and RNA-seq reveal ATRA coordinated SE waves. SEs that decrease with ATRA link to stem cell development (MYCN, GATA3, SOX11). CRISPR-Cas9 and siRNA verify SOX11 dependency, in vitro and in vivo. Silencing the SOX11 SE using dCAS9-KRAB decreases SOX11 mRNA and inhibits cell growth. Other TFs activate in sequential waves at 2, 4 and 8 days of ATRA treatment that regulate neural development (GATA2 and SOX4). Silencing the gained SOX4 SE using dCAS9-KRAB decreases SOX4 expression and attenuates ATRA-induced differentiation genes. Our study identifies oncogenic lineage drivers of NB self-renewal and TFs critical for implementing a differentiation program.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CRISPR-Cas Systems
  • Cell Differentiation* / drug effects
  • Cell Differentiation* / genetics
  • Cell Line, Tumor
  • Cell Lineage / genetics
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Cell Self Renewal / drug effects
  • Cell Self Renewal / genetics
  • GATA2 Transcription Factor / genetics
  • GATA2 Transcription Factor / metabolism
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / metabolism
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • N-Myc Proto-Oncogene Protein / genetics
  • N-Myc Proto-Oncogene Protein / metabolism
  • Neuroblastoma* / genetics
  • Neuroblastoma* / metabolism
  • Neuroblastoma* / pathology
  • SOXC Transcription Factors* / genetics
  • SOXC Transcription Factors* / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tretinoin* / metabolism
  • Tretinoin* / pharmacology


  • Tretinoin
  • SOXC Transcription Factors
  • Transcription Factors
  • SOX11 protein, human
  • GATA3 Transcription Factor
  • SOX4 protein, human
  • GATA3 protein, human
  • GATA2 Transcription Factor
  • N-Myc Proto-Oncogene Protein