A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma

Tim Groningen, Nurdan Akogul, Ellen M. Westerhout, Alvin Chan, Nancy E. Hasselt, Danny A. Zwijnenburg, Marloes Broekmans, Peter Stroeken, Franciska Haneveld, Gerrit K. J. Hooijer, C. Dilara Savci-Heijink, Arjan Lakeman, Richard Volckmann, Peter Sluis, Linda J. Valentijn, Jan Koster, Rogier Versteeg and Johan Nes ()
Additional contact information
Tim Groningen: Amsterdam UMC University of Amsterdam
Nurdan Akogul: Amsterdam UMC University of Amsterdam
Ellen M. Westerhout: Amsterdam UMC University of Amsterdam
Alvin Chan: Amsterdam UMC University of Amsterdam
Nancy E. Hasselt: Amsterdam UMC University of Amsterdam
Danny A. Zwijnenburg: Amsterdam UMC University of Amsterdam
Marloes Broekmans: Amsterdam UMC University of Amsterdam
Peter Stroeken: Amsterdam UMC University of Amsterdam
Franciska Haneveld: Amsterdam UMC University of Amsterdam
Gerrit K. J. Hooijer: Amsterdam UMC University of Amsterdam
C. Dilara Savci-Heijink: Amsterdam UMC University of Amsterdam
Arjan Lakeman: Amsterdam UMC University of Amsterdam
Richard Volckmann: Amsterdam UMC University of Amsterdam
Peter Sluis: Amsterdam UMC University of Amsterdam
Linda J. Valentijn: Amsterdam UMC University of Amsterdam
Jan Koster: Amsterdam UMC University of Amsterdam
Rogier Versteeg: Amsterdam UMC University of Amsterdam
Johan Nes: Amsterdam UMC University of Amsterdam

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: Abstract Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood. The pediatric cancer neuroblastoma includes adrenergic (ADRN) and mesenchymal (MES) tumor cell types, which differ in phenotype, super-enhancers (SEs) and core regulatory circuitries. These cell types can spontaneously interconvert, but the mechanism remains largely unknown. Here, we unravel how a NOTCH3 intracellular domain reprogrammed the ADRN transcriptional landscape towards a MES state. A transcriptional feed-forward circuitry of NOTCH-family transcription factors amplifies the NOTCH signaling levels, explaining the swift transition between two semi-stable cellular states. This transition induces genome-wide remodeling of the H3K27ac landscape and a switch from ADRN SEs to MES SEs. Once established, the NOTCH feed-forward loop maintains the induced MES state. In vivo reprogramming of ADRN cells shows that MES and ADRN cells are equally oncogenic. Our results elucidate a swift transdifferentiation between two semi-stable epigenetic cellular states.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (4)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-09470-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09470-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-09470-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().