title: Inference of gene regulation functions from dynamic transcriptome data.
abstract: To quantify gene regulation, a function is required that relates transcription factor binding to DNA (input) to the rate of mRNA synthesis from a target gene (output). Such a 'gene regulation function' (GRF) generally cannot be measured because the experimental titration of inputs and simultaneous readout of outputs is difficult. Here we show that GRFs may instead be inferred from natural changes in cellular gene expression, as exemplified for the cell cycle in the yeastS. cerevisiae. We develop this inference approach based on a time series of mRNA synthesis rates from a synchronized population of cells observed over three cell cycles. We first estimate the functional form of how input transcription factors determine mRNA output and then derive GRFs for target genes in theCLB2gene cluster that are expressed during G2/M phase. Systematic analysis of additional GRFs suggests a network architecture that rationalizes transcriptional cell cycle oscillations. We find that a transcription factor network alone can produce oscillations in mRNA expression, but that additional input from cyclin oscillations is required to arrive at the native behaviour of the cell cycle oscillator.
authors.affiliation: Lehrstuhl für Theorie komplexer Biosysteme, Physik-Department, Technische Universität München, Garching, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Hillenbrand
authors.affiliation: Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Kerstin C
authors.initials: KC
authors.lastname: Maier
authors.affiliation: Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany.
authors.forename: Patrick
authors.identifier: 0000-0001-5454-7755
authors.initials: P
authors.lastname: Cramer
authors.affiliation: Lehrstuhl für Theorie komplexer Biosysteme, Physik-Department, Technische Universität München, Garching, Germany.
authors.forename: Ulrich
authors.identifier: 0000-0002-0859-6422
authors.initials: U
authors.lastname: Gerland
mesh_terms: D002453:Cell Cycle; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D005810:Multigene Family; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000502:physiology; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014157:Transcription Factors
keywords: S. cerevisiae; cell cycle; computational biology; gene regulation; network inference; quantitative biology; systems biology