Gene Networks with Transcriptional Bursting Recapitulate Rare Transient Coordinated High Expression States in Cancer.

Autor:	Schuh L; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg 85764, Germany; Department of Mathematics, Technical University of Munich, Garching 85748, Germany., Saint-Antoine M; Center for Bioinformatics and Computational Biology, University of Delaware, Newark, DE 19716, USA., Sanford EM; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA., Emert BL; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA., Singh A; Electrical and Computer Engineering, University of Delaware, Newark, DE 19716, USA., Marr C; Helmholtz Zentrum München-German Research Center for Environmental Health, Institute of Computational Biology, Neuherberg 85764, Germany., Raj A; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA., Goyal Y; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA. Electronic address: yogesh.goyal0308@gmail.com.
Jazyk:	angličtina
Zdroj:	Cell systems [Cell Syst] 2020 Apr 22; Vol. 10 (4), pp. 363-378.e12.
DOI:	10.1016/j.cels.2020.03.004
Abstrakt:	Non-genetic transcriptional variability is a potential mechanism for therapy resistance in melanoma. Specifically, rare subpopulations of cells occupy a transient pre-resistant state characterized by coordinated high expression of several genes and survive therapy. How might these rare states arise and disappear within the population? It is unclear whether the canonical models of probabilistic transcriptional pulsing can explain this behavior, or if it requires special, hitherto unidentified mechanisms. We show that a minimal model of transcriptional bursting and gene interactions can give rise to rare coordinated high expression states. These states occur more frequently in networks with low connectivity and depend on three parameters. While entry into these states is initiated by a long transcriptional burst that also triggers entry of other genes, the exit occurs through independent inactivation of individual genes. Together, we demonstrate that established principles of gene regulation are sufficient to describe this behavior and argue for its more general existence. A record of this paper's transparent peer review process is included in the Supplemental Information. Competing Interests: Declaration of Interests A.R. receives royalties related to Stellaris RNA FISH probes. All other authors declare no competing interests. (Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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