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

Deblina Banerjee; Sukriti Bagchi; Zhihui Liu; Hsien-Chao Chou; Man Xu; Ming Sun; Sara Aloisi; Zalman Vaksman; Sharon J Diskin; Mark Zimmerman; Javed Khan; Berkley Gryder; Carol J Thiele

doi:10.1038/s41467-024-47166-y

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.

Authors

Deblina Banerjee^#¹, Sukriti Bagchi², Zhihui Liu², Hsien-Chao Chou³, Man Xu², Ming Sun², Sara Aloisi^{4

5}, Zalman Vaksman⁶, Sharon J Diskin⁷, Mark Zimmerman⁸, Javed Khan³, Berkley Gryder^#⁹, Carol J Thiele¹⁰

Affiliations

¹ Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. [email protected].
² Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
³ Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
⁴ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁵ Department of Pharmacy and Biotechnology, University of Bologna, Bologna, 40126, Italy.
⁶ New York Genome Center, New York, NY, 10013, USA.
⁷ Department of Pediatrics, Division of Oncology, Perelman School of Medicine, Philadelphia, PA, USA.
⁸ Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
⁹ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA. [email protected].
¹⁰ Cell & Molecular Biology Section, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. [email protected].

^# Contributed equally.

Abstract

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

Substances

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