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

Harada, T.; Kalfon, J.; Perez, M. W.; Eagle, K.; Braes, F. D.; Batley, R.; Heshmati, Y.; Ferrucio, J. X.; Ewers, J.; Mehta, S.; Kossenkov, A.; Ellegast, J. M.; Bowker, A.; Wickramasinghe, J.; Nabet, B.; Paralkar, V. R.; Dharia, N. V.; Stegmaier, K.; Orkin, S. H.; Pimkin, M.

doi:10.1101/2023.03.13.532438

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bioRxiv · 10.1101/2023.03.13.532438

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

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Abstract

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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Harada, T., Kalfon, J., Perez, M. W., Eagle, K., Braes, F. D., Batley, R., Heshmati, Y., Ferrucio, J. X., Ewers, J., Mehta, S., Kossenkov, A., Ellegast, J. M., Bowker, A., Wickramasinghe, J., Nabet, B., Paralkar, V. R., Dharia, N. V., Stegmaier, K., Orkin, S. H., Pimkin, M.. 2023-03-15. Leukemia core transcriptional circuitry is a sparsely interconnected hierarchy stabilized by incoherent feed-forward loops. https://doi.org/10.1101/2023.03.13.532438

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