@article{3928a2fbee024a3db6fef9e2ab35e31d,
title = "Gene Networks with Transcriptional Bursting Recapitulate Rare Transient Coordinated High Expression States in Cancer",
abstract = "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.",
keywords = "drug resistance, gene expression, melanoma, network, non-genetic, stochasticity",
author = "Lea Schuh and Michael Saint-Antoine and Sanford, {Eric M.} and Emert, {Benjamin L.} and Abhyudai Singh and Carsten Marr and Arjun Raj and Yogesh Goyal",
note = "Funding Information: We thank the Raj lab members, especially Ian Mellis and Amy Azaria, for scientific discussions and comments on the manuscript. We also thank Ravi Radhakrishnan and Alok Ghosh for helpful discussion during the initial stages of this project. We thank Cesar A Vargas-Garcia for his help during the initial discussions on network inference. L.S. would like to acknowledge the support of the PROMOS fellowship of the DAAD, Germany. L.S. was funded by the BMBF project TIDY ( 031L0170B ) and financially supported by the Entrepreneurial Award within the program {\textquoteleft}Global Challenges for Women in Math Science{\textquoteright} of the Department of Mathematics, Technical University of Munich. B.L.E. acknowledges support from NIH F30 CA236129 and Patel Family Scholars award. A.S. acknowledges support from the NIH grant 5R01GM124446-02 and ARO grant W911NF-19-1-0243 . C.M. acknowledges support from the Deutsche Forschungsgemeinschaft DFG through the SFB 1243 . A.R. acknowledges support from NIH/ NCI PSOC U54 CA193417 , NSF CAREER 1350601 , P30 CA016520 , SPORE P50 CA174523 , NIH U01 CA227550 , NIH 4DN U01 HL129998 , NIH Center for Photogenomics RM1 HG007743 , NIH R01 CA232256 , NIH R01 CA238237 , NIH R01 GM137425 , and the Tara Miller Foundation . Y.G. would like to acknowledge the Schmidt Science Fellows in partnership with the Rhodes Trust. Y.G. is a fellow of the Jane Coffin Childs Memorial Fund for Medical Research and this investigation has been aided by a grant from the Jane Coffin Childs Memorial Fund for Medical Research . Funding Information: We thank the Raj lab members, especially Ian Mellis and Amy Azaria, for scientific discussions and comments on the manuscript. We also thank Ravi Radhakrishnan and Alok Ghosh for helpful discussion during the initial stages of this project. We thank Cesar A Vargas-Garcia for his help during the initial discussions on network inference. L.S. would like to acknowledge the support of the PROMOS fellowship of the DAAD, Germany. L.S. was funded by the BMBF project TIDY (031L0170B) and financially supported by the Entrepreneurial Award within the program {\textquoteleft}Global Challenges for Women in Math Science{\textquoteright} of the Department of Mathematics, Technical University of Munich. B.L.E. acknowledges support from NIH F30 CA236129 and Patel Family Scholars award. A.S. acknowledges support from the NIH grant 5R01GM124446-02 and ARO grant W911NF-19-1-0243. C.M. acknowledges support from the Deutsche Forschungsgemeinschaft DFG through the SFB 1243. A.R. acknowledges support from NIH/NCI PSOC U54 CA193417, NSF CAREER 1350601, P30 CA016520, SPORE P50 CA174523, NIH U01 CA227550, NIH 4DN U01 HL129998, NIH Center for Photogenomics RM1 HG007743, NIH R01 CA232256, NIH R01 CA238237, NIH R01 GM137425, and the Tara Miller Foundation. Y.G. would like to acknowledge the Schmidt Science Fellows in partnership with the Rhodes Trust. Y.G. is a fellow of the Jane Coffin Childs Memorial Fund for Medical Research and this investigation has been aided by a grant from the Jane Coffin Childs Memorial Fund for Medical Research. Conceptualization, A.R. and Y.G.; Methodology, L.S. Y.G. and A.R.; Software, L.S. and A.R.; Validation, L.S.; Formal Analysis, L.S. and M.S.-A.; Resources, A.R. and A.S.; Investigation, E.M.S. Y.G. and B.L.E.; Data Curation, L.S. and Y.G.; Writing – Original Draft, Y.G.; Writing – Review & Editing, A.R. L.S. Y.G. C.M. E.M.S. B.L.E. and M.S.-A.; Visualization, L.S. and Y.G.; Supervision, Y.G. A.R. and C.M.; Project Administration, Y.G. and A.R.; Funding Acquisition, A.R. A.S. and C.M. A.R. receives royalties related to Stellaris RNA FISH probes. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2020",
month = apr,
day = "22",
doi = "10.1016/j.cels.2020.03.004",
language = "English (US)",
volume = "10",
pages = "363--378.e12",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "4",
}
