title: A Systematic Ensemble Approach to Thermodynamic Modeling of Gene Expression from Sequence Data.
abstract: To understand the relationship between an enhancer DNA sequence and quantitative gene expression, thermodynamics-driven mathematical models of transcription are often employed. These "sequence-to-expression" models can describe an incomplete or even incorrect set of regulatory relationships if the parameter space is not searched systematically. Here, we focus on an enhancer of the Drosophila gene ind and demonstrate how a systematic search of parameter space can reveal a more comprehensive picture of a gene's regulatory mechanisms, resolve outstanding ambiguities, and suggest testable hypotheses. We describe an approach that generates an ensemble of ind models; all of these models are technically acceptable solutions to the sequence-to-expression problem in light of wild-type data, and some represent mechanistically distinct hypotheses about the regulation of ind. This ensemble can be restricted to biologically plausible models using requirements gleaned from in vivo perturbation experiments. Biologically plausible models make unique predictions about how specific ind enhancer sequences affect ind expression; we validate these predictions in vivo through site mutagenesis in transgenic Drosophila embryos.
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
authors.forename: Md Abul Hassan
authors.initials: MA
authors.lastname: Samee
authors.affiliation: Department of Chemical and Biological Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Bomyi
authors.initials: B
authors.lastname: Lim
authors.affiliation: Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08208, Spain.
authors.forename: Núria
authors.initials: N
authors.lastname: Samper
authors.affiliation: School of Chemical and Biomolecular Engineering and Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Biology, New York University, New York, NY 10003, USA.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Rushlow
authors.affiliation: Department of Developmental Biology, Instituto de Biología Molecular de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Barcelona 08208, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Jiménez
authors.affiliation: Department of Chemical and Biological Engineering and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544, USA.
authors.forename: Stanislav Y
authors.initials: SY
authors.lastname: Shvartsman
authors.affiliation: Department of Computer Science, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: sinhas@illinois.edu.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Sinha