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Leukemia core transcriptional circuitry is a sparsely interconnected hierarchy stabilized by incoherent feed-forward loops.

Taku HaradaJérémie KalfonMonika W PerezKenneth EagleFlora Dievenich BraesRashad BatleyYaser HeshmatiJuliana Xavier FerrucioJazmin EwersStuti MehtaAndrew KossenkovJana M EllegastAllyson BowkerJayamanna WickramasingheBehnam NabetVikram R ParalkarNeekesh V DhariaKimberly StegmaierStuart H OrkinMaxim Pimkin
Published in: bioRxiv : the preprint server for biology (2023)
Lineage-defining transcription factors form densely interconnected circuits in chromatin occupancy assays, but the functional significance of these networks remains underexplored. We reconstructed the functional topology of a leukemia cell transcription network from the direct gene-regulatory programs of eight core transcriptional regulators established in pre-steady state assays coupling targeted protein degradation with nascent transcriptomics. The core regulators displayed narrow, largely non-overlapping direct transcriptional programs, forming a sparsely interconnected functional hierarchy stabilized by incoherent feed-forward loops. BET bromodomain and CDK7 inhibitors disrupted the core regulators' direct programs, acting as mixed agonists/antagonists. The network is predictive of dynamic gene expression behaviors in time-resolved assays and clinically relevant pathway activity in patient populations.
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