BioRxiv
bioRxiv Subject Collection: Systems Biology
This feed contains articles for bioRxiv Subject Collection "Systems Biology"
Leukemia core transcriptional circuitry is a sparsely interconnected hierarchy stabilized by incoherent feed-forward loops
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.
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.
March 16, 2023
http://biorxiv.org/cgi/content/short/2023.03.13.532438v1?rss=1