Bayesian inference and comparison of stochastic transcription elongation models

PLoS Comput Biol. 2020 Feb 14;16(2):e1006717. doi: 10.1371/journal.pcbi.1006717. eCollection 2020 Feb.

Abstract

Transcription elongation can be modelled as a three step process, involving polymerase translocation, NTP binding, and nucleotide incorporation into the nascent mRNA. This cycle of events can be simulated at the single-molecule level as a continuous-time Markov process using parameters derived from single-molecule experiments. Previously developed models differ in the way they are parameterised, and in their incorporation of partial equilibrium approximations. We have formulated a hierarchical network comprised of 12 sequence-dependent transcription elongation models. The simplest model has two parameters and assumes that both translocation and NTP binding can be modelled as equilibrium processes. The most complex model has six parameters makes no partial equilibrium assumptions. We systematically compared the ability of these models to explain published force-velocity data, using approximate Bayesian computation. This analysis was performed using data for the RNA polymerase complexes of E. coli, S. cerevisiae and Bacteriophage T7. Our analysis indicates that the polymerases differ significantly in their translocation rates, with the rates in T7 pol being fast compared to E. coli RNAP and S. cerevisiae pol II. Different models are applicable in different cases. We also show that all three RNA polymerases have an energetic preference for the posttranslocated state over the pretranslocated state. A Bayesian inference and model selection framework, like the one presented in this publication, should be routinely applicable to the interrogation of single-molecule datasets.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacteriophage T7 / enzymology
  • Bayes Theorem*
  • DNA-Directed RNA Polymerases / metabolism
  • Escherichia coli / enzymology
  • Kinetics
  • Markov Chains
  • Models, Genetic*
  • Saccharomyces cerevisiae
  • Stochastic Processes*
  • Transcription, Genetic*

Substances

  • DNA-Directed RNA Polymerases

Grants and funding

J. Douglas was funded by a University of Auckland Doctoral Scholarship. URL: https://www.auckland.ac.nz/en/study/scholarships-and-awards/scholarship-types/postgraduate-scholarships/doctoral-scholarships.html. The authors wish to acknowledge the contribution of NeSI high-performance computing facilities to the results of this research. NZ’s national facilities are provided by the NZ eScience Infrastructure and funded jointly by NeSI’s collaborator institutions and through the Ministry of Business, Innovation & Employment’s Research Infrastructure programme. URL https://www.nesi.org.nz. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.