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 PimkinPublished 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.
Keyphrases
- transcription factor
- gene expression
- single cell
- high throughput
- dna binding
- public health
- acute myeloid leukemia
- dna methylation
- bone marrow
- contrast enhanced
- magnetic resonance imaging
- diffusion weighted
- case report
- small molecule
- diffusion weighted imaging
- mesenchymal stem cells
- cell cycle
- protein protein
- cell therapy