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Boswell, Sarah

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Boswell

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Sarah

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Boswell, Sarah
Author's Publications: search.filters.isAuthorOfPublication.192d8440-3eaf-4e0b-bc3a-a5c1962bd9fe

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    SnapShot-Seq: A Method for Extracting Genome-Wide, In Vivo mRNA Dynamics from a Single Total RNA Sample
    (Public Library of Science, 2014) Gray, Jesse; Harmin, David; Boswell, Sarah; Cloonan, Nicole; Mullen, Thomas E.; Ling, Joseph J.; Miller, Nimrod; Kuersten, Scott; Ma, Yong-Chao; McCarroll, Steven; Grimmond, Sean M.; Springer, Michael
    mRNA synthesis, processing, and destruction involve a complex series of molecular steps that are incompletely understood. Because the RNA intermediates in each of these steps have finite lifetimes, extensive mechanistic and dynamical information is encoded in total cellular RNA. Here we report the development of SnapShot-Seq, a set of computational methods that allow the determination of in vivo rates of pre-mRNA synthesis, splicing, intron degradation, and mRNA decay from a single RNA-Seq snapshot of total cellular RNA. SnapShot-Seq can detect in vivo changes in the rates of specific steps of splicing, and it provides genome-wide estimates of pre-mRNA synthesis rates comparable to those obtained via labeling of newly synthesized RNA. We used SnapShot-Seq to investigate the origins of the intrinsic bimodality of metazoan gene expression levels, and our results suggest that this bimodality is partly due to spillover of transcriptional activation from highly expressed genes to their poorly expressed neighbors. SnapShot-Seq dramatically expands the information obtainable from a standard RNA-Seq experiment.
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    Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de‐differentiated state
    (John Wiley and Sons Inc., 2017) Fallahi‐Sichani, Mohammad; Becker, Verena; Izar, Benjamin; Baker, Gregory; Lin, Jia‐Ren; Boswell, Sarah; Shah, Parin; Rotem, Asaf; Garraway, Levi; Sorger, Peter
    Abstract Treatment of BRAF‐mutant melanomas with MAP kinase pathway inhibitors is paradigmatic of the promise of precision cancer therapy but also highlights problems with drug resistance that limit patient benefit. We use live‐cell imaging, single‐cell analysis, and molecular profiling to show that exposure of tumor cells to RAF/MEK inhibitors elicits a heterogeneous response in which some cells die, some arrest, and the remainder adapt to drug. Drug‐adapted cells up‐regulate markers of the neural crest (e.g., NGFR), a melanocyte precursor, and grow slowly. This phenotype is transiently stable, reverting to the drug‐naïve state within 9 days of drug withdrawal. Transcriptional profiling of cell lines and human tumors implicates a c‐Jun/ECM/FAK/Src cascade in de‐differentiation in about one‐third of cell lines studied; drug‐induced changes in c‐Jun and NGFR levels are also observed in xenograft and human tumors. Drugs targeting the c‐Jun/ECM/FAK/Src cascade as well as BET bromodomain inhibitors increase the maximum effect (E max) of RAF/MEK kinase inhibitors by promoting cell killing. Thus, analysis of reversible drug resistance at a single‐cell level identifies signaling pathways and inhibitory drugs missed by assays that focus on cell populations.