Inference of gene regulation functions from dynamic transcriptome data

Abstract
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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 yeast S. 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 the clb2 gene 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.

Data availability

The following previously published data sets were used

1. Eser P
2. Demel C
3. Maier K
4. Schwalb B
5. Pirkl N
6. Cramer P
7. Tresch A
(2014) Transcription profiling by array of Saccharomyces cerevisiae cells to estimate labeled and total mRNA levels every 5 minutes for three complete cell cycles
E-MTAB-1908.

https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-1908/

Article and author information

Author details

Patrick Hillenbrand

Department of Physics, Technical University of Munich, Garching, Germany

Competing interests
No competing interests declared.
Kerstin C Maier

Department of Molecular Biology, Max-Planck Institute for Biophysical Chemistry, Göttingen, Germany

Competing interests
No competing interests declared.
Patrick Cramer

Department of Molecular Biology, Max Planck Institute for Biophysical Chemistry, Göttingen, Germany

Competing interests
Patrick Cramer, Reviewing editor, eLife.

"This ORCID iD identifies the author of this article:" 0000-0001-5454-7755
Ulrich Gerland

Department of Physics, Technical University of Munich, Garching, Germany

For correspondence
gerland@tum.de

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-0859-6422

Funding

Deutsche Forschungsgemeinschaft

Patrick Cramer
Ulrich Gerland

Volkswagen Foundation

Patrick Cramer

Bayerisches Staatsministerium für Bildung und Kultus, Wissenschaft und Kunst

Ulrich Gerland

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.