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.
Highlights
Transition between differentiation states in development occurs swift but the mechanisms leading to epigenetic and transcriptional reprogramming are poorly understood
Experimental models of induced Pluripotent Stem Cells or direct conversion of lineage-committed cells have provided a wealth of information on signaling molecules, gene transcription, and chromatin states that underlie the reprogramming of cellular fate
NOTCH-IC translocates to the nucleus, where it forms a transcriptional complex with a mastermind-like (MAML) coactivator and the DNA-binding protein CSL
Summary
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. The distinct cell populations detected in glioblastoma and neuroblastoma have unique enhancer and super-enhancer (SE) landscapes[1,2,6] These SEs are associated with expression of lineage transcription factors (TFs) that constitute the Core Regulatory Circuitry (CRC) for each cell type. Overexpression of PRRX1, a MESspecific CRC TF, was found to reprogram the transcriptional- and epigenetic landscapes of ADRN cells towards a MES state[1] This shows that CRC TFs are potent inducers of lineage identity. This complex regulates expression of Notch target genes[14,15,16] including lineagespecific TFs to instruct cell fate decisions[10]
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