TY - JOUR
T1 - A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma
AU - van Groningen, Tim
AU - Akogul, Nurdan
AU - Westerhout, Ellen M.
AU - Chan, Alvin
AU - Hasselt, Nancy E.
AU - Zwijnenburg, Danny A.
AU - Broekmans, Marloes
AU - Stroeken, Peter
AU - Haneveld, Franciska
AU - Hooijer, Gerrit K. J.
AU - Savci-Heijink, C. Dilara
AU - Lakeman, Arjan
AU - Volckmann, Richard
AU - van Sluis, Peter
AU - Valentijn, Linda J.
AU - Koster, Jan
AU - Versteeg, Rogier
AU - van Nes, Johan
PY - 2019/4/4
Y1 - 2019/4/4
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063995095&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30948783
U2 - https://doi.org/10.1038/s41467-019-09470-w
DO - https://doi.org/10.1038/s41467-019-09470-w
M3 - Article
C2 - 30948783
SN - 2041-1723
VL - 10
SP - 1530
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 1530
ER -