Notch1 mediates stage-specific dynamic transcriptional networks during early T-cell development

Notch1 signaling is essential to initiate and sustain T-cell development from early thymic progenitors (ETPs) to pre-T cells. How Notch orchestrates T cell lineage commitment remains an open question. Integrating multi-omics platforms of bulk RNA-Seq, ChIP-Seq, mass spectrometry, and HiC we identified 46 transcription factors (TFs) regulated by Notch1 via super-enhancers that mediate stage-specific transcriptional networks progressively during T cell commitment. Six of these TFs form a supramolecular complex with Notch1. Among those, ERG and FLI1 are essential very early, and the lack of both impaired the attenuation of stem cell and lineage programs. Ultimately, this led to conflicting transcriptional programs, hastened T-cell development, and apoptosis, emphasizing the importance of progressive acquisition of T cell identity.