Inferring delays in partially observed gene regulatory networks

Abstract

Motivation: Cell function is regulated by gene regulatory networks (GRNs) defined by protein-mediated interaction between constituent genes. Despite advances in experimental techniques, we can still measure only a fraction of the processes that govern GRN dynamics. To infer the properties of GRNs using partial observation, unobserved sequential processes can be replaced with distributed time delays, yielding non- Markovian models. Inference methods based on the resulting model suffer from the curse of dimensionality. Results: We develop a simulation-based Bayesian MCMC method for the efficient and accurate inference of GRN parameters when only some of their products are observed. We illustrate our approach using a two-step activation model: An activation signal leads to the accumulation of an unobserved regulatory protein, which triggers the expression of observed fluorescent proteins. With prior information about observed fluorescent protein synthesis, our method successfully infers the dynamics of the unobserved regulatory protein. We can estimate the delay and kinetic parameters characterizing target regulation including transcription, translation, and target searching of an unobserved protein from experimental measurements of the products of its target gene. Our method is scalable and can be used to analyze non-Markovian models with hidden components. Availability: Accompanying code in R is available at https://github.com/Mathbiomed/SimMCMC.

Noisy delay denoises biochemical oscillators

“…Although fixed delay has been widely used to investigate biological systems [11][12][13][14], assuming a distributed delay is more realistic due to the inherent stochasticity associated with the numerous reactions required for protein synthesis [25,26,28,29]. Thus, we now investigate the impact of a distributed delay on the stochastic oscillator.…”