A NOTCH feed-forward loop drives reprogramming from adrenergic to mesenchymal state in neuroblastoma
| Autor: | Richard Volckmann, Ellen M. Westerhout, C. Dilara Savci-Heijink, Alvin Chan, Tim van Groningen, Gerrit K. J. Hooijer, Linda J. Valentijn, Franciska Haneveld, Peter Stroeken, Arjan Lakeman, Jan Koster, Johan van Nes, Nancy E. Hasselt, Danny A. Zwijnenburg, Marloes Broekmans, Peter van Sluis, Nurdan Akogul, Rogier Versteeg |
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| Přispěvatelé: | Graduate School, Oncology, CCA - Cancer biology and immunology, Oncogenomics, Pathology |
| Rok vydání: | 2019 |
| Předmět: |
Adrenergic Neurons
0301 basic medicine Cell type animal structures Science Notch signaling pathway General Physics and Astronomy 02 engineering and technology Biology Article General Biochemistry Genetics and Molecular Biology Epigenesis Genetic Neuroblastoma 03 medical and health sciences Cell Line Tumor Humans Epigenetics lcsh:Science Receptor Notch3 Transcription factor Feedback Physiological Regulation of gene expression Multidisciplinary Gene Expression Profiling Transdifferentiation Mesenchymal Stem Cells General Chemistry Cellular Reprogramming 021001 nanoscience & nanotechnology Pediatric cancer Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology lcsh:Q 0210 nano-technology Reprogramming |
| Zdroj: | Nature communications, 10(1):1530. Nature Publishing Group Nature Communications, Vol 10, Iss 1, Pp 1-11 (2019) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-09470-w |
| Popis: | 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. Neuroblastoma includes adrenergic and mesenchymal cell types that can interconvert. Here, the authors show that this transdifferentiation is driven by a NOTCH feedforward loop that allows a swift transition between two semi-stable cellular states. |
| Databáze: | OpenAIRE |
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