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  • 1.
    Belliveau, Nathan M.
    et al.
    CALTECH, Div Biol & Biol Engn, Pasadena, USA.
    Barnes, Stephanie L.
    CALTECH, Div Biol & Biol Engn, Pasadena, USA.
    Ireland, William T.
    CALTECH, Dept Phys, Pasadena, USA.
    Jones, Daniel L.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Sweredoski, Michael J.
    CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, USA.
    Moradian, Annie
    CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, USA.
    Hess, Sonja
    CALTECH, Beckman Inst, Proteome Explorat Lab, Pasadena, CA 91125 USA;MedImmune, Antibody Discovery & Prot Engn, Gaithersburg, USA.
    Kinney, Justin B.
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, USA.
    Phillips, Rob
    CALTECH, Div Biol & Biol Engn, Pasadena, USA;CALTECH, Dept Phys, Pasadena, CA 91125 USA;CALTECH, Dept Appl Phys, Pasadena, CA 91125 USA.
    Systematic approach for dissecting the molecular mechanisms of transcriptional regulation in bacteria2018In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, no 21, p. E4796-E4805Article in journal (Refereed)
    Abstract [en]

    Gene regulation is one of the most ubiquitous processes in biology. However, while the catalog of bacterial genomes continues to expand rapidly, we remain ignorant about how almost all of the genes in these genomes are regulated. At present, characterizing the molecular mechanisms by which individual regulatory sequences operate requires focused efforts using low-throughput methods. Here, we take a first step toward multipromoter dissection and show how a combination of massively parallel reporter assays, mass spectrometry, and information-theoretic modeling can be used to dissect multiple bacterial promoters in a systematic way. We show this approach on both well-studied and previously uncharacterized promoters in the enteric bacterium Escherichia coli. In all cases, we recover nucleotide-resolution models of promoter mechanism. For some promoters, including previously unannotated ones, the approach allowed us to further extract quantitative biophysical models describing input-output relationships. Given the generality of the approach presented here, it opens up the possibility of quantitatively dissecting the mechanisms of promoter function in E. coli and a wide range of other bacteria.

  • 2.
    Forcier, Talitha L.
    et al.
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA.
    Ayaz, Andalus
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA.
    Gill, Manraj S.
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA;MIT, Dept Biol, Cambridge, MA 02139 USA.
    Jones, Daniel
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA;CALTECH, Dept Appl Phys, Pasadena, CA 91125 USA.
    Phillips, Rob
    CALTECH, Dept Appl Phys, Pasadena, CA 91125 USA.
    Kinney, Justin B.
    Cold Spring Harbor Lab, Simons Ctr Quantitat Biol, POB 100, Cold Spring Harbor, NY 11724 USA.
    Measuring cis-regulatory energetics in living cells using allelic manifolds2018In: eLIFE, E-ISSN 2050-084X, Vol. 7, article id e40618Article in journal (Refereed)
    Abstract [en]

    Gene expression in all organisms is controlled by cooperative interactions between DNA-bound transcription factors (TFs), but quantitatively measuring TF-DNA and TF-TF interactions remains difficult. Here we introduce a strategy for precisely measuring the Gibbs free energy of such interactions in living cells. This strategy centers on the measurement and modeling of 'allelic manifolds', a multidimensional generalization of the classical genetics concept of allelic series. Allelic manifolds are measured using reporter assays performed on strategically designed cis-regulatory sequences. Quantitative biophysical models are then fit to the resulting data. We used this strategy to study regulation by two Escherichia coli TFs, CRP and sigma(70) RNA polymerase. Doing so, we consistently obtained energetic measurements precise to similar to 0.1 kcal/mol. We also obtained multiple results that deviate from the prior literature. Our strategy is compatible with massively parallel reporter assays in both prokaryotes and eukaryotes, and should therefore be highly scalable and broadly applicable.

    Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that minor issues remain unresolved (see decision letter).

  • 3.
    Jones, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elf, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Bursting onto the scene?: Exploring stochastic mRNA production in bacteria2018In: Current Opinion in Microbiology, ISSN 1369-5274, E-ISSN 1879-0364, Vol. 45, p. 124-130Article, review/survey (Refereed)
    Abstract [en]

    Recent large-scale measurements of gene expression variability (or noise) in E. coli have led to the unexpected conclusion that the variability is in large part dictated by and increasing with the mean level of expression. Here we review the evidence for this apparent universal trend in variability, as well as for the related idea that transcription is fundamentally bursty. We examine recently proposed mechanisms for burstiness and universality and argue that they do not explain important features of observed data. Finally, we discuss potential limitations and pitfalls in the interpretation of experimental measurements of cell-to-cell variability.

  • 4.
    Jones, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Leroy, Prune
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Unoson, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fange, David
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Curic, Vladimir
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lawson, Michael J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elf, Johan
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology. Uppsala Univ, Dept Cell & Mol Biol, Sci Life Lab, Uppsala, Sweden..
    Kinetics of dCas9 target search in Escherichia coli2017In: Science, ISSN 0036-8075, E-ISSN 1095-9203, Vol. 357, no 6358, p. 1420-1423Article in journal (Refereed)
    Abstract [en]

    How fast can a cell locate a specific chromosomal DNA sequence specified by a single-stranded oligonucleotide? To address this question, we investigate the intracellular search processes of the Cas9 protein, which can be programmed by a guide RNA to bind essentially any DNA sequence. This targeting flexibility requires Cas9 to unwind the DNA double helix to test for correct base pairing to the guide RNA. Here we study the search mechanisms of the catalytically inactive Cas9 (dCas9) in living Escherichia coli by combining single-molecule fluorescence microscopy and bulk restriction-protection assays. We find that it takes a single fluorescently labeled dCas9 6 hours to find the correct target sequence, which implies that each potential target is bound for less than 30 milliseconds. Once bound, dCas9 remains associated until replication. To achieve fast targeting, both Cas9 and its guide RNA have to be present at high concentrations.

  • 5.
    Jones, Daniel
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Unoson, Cecilia
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Leroy, Prune
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Curic, Vladimir
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Elf, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Systems Biology.
    Kinetics of dCas9 Target Search in Escherichia Coli2017In: Biophysical Journal, ISSN 0006-3495, E-ISSN 1542-0086, Vol. 112, no 3, p. 314A-314AArticle in journal (Other academic)
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