Stochastic modeling of human papillomavirusearly promoter gene regulation

Abstract

High risk forms of human papillomaviruses (HPVs) promote cancerous lesions and are implicated in almost all cervical cancer. Of particular relevance to cancer progression is regulation of the early promoter that controls gene expression in the initial phases of infection and can eventually lead to pre-cancer progression. Our goal was to develop a stochastic model to investigate the control mechanisms that regulate gene expression from the HPV early promoter. Our model integrates modules that account for transcriptional, post-transcriptional, translational and post-translational regulation of E1 and E2 early genes to form a functioning gene regulatory network. Each module consists of a set of biochemical steps whose stochastic evolution is governed by a chemical Master Equation and can be simulated using the Gillespie algorithm. To investigate the role of noise in gene expression, we compared our stochastic simulations with solutions to ordinary differential equations for the mean behavior of the system that are valid under the conditions of large molecular abundances and quasi-equilibrium for fast reactions. The model produced results consistent with known HPV biology. Our simulation results suggest that stochasticity plays a pivotal role in determining the dynamics of HPV gene expression. In particular, the combination of positive and negative feedback regulation generates stochastic bursts of gene expression. Analysis of the model reveals that regulation at the promoter affects burst amplitude and frequency, whereas splicing is more specialized to regulate burst frequency. Our results also suggest that splicing enhancers are a significant source of stochasticity in pre-mRNA abundance and that the number of viruses infecting the host cell represents a third important source of stochasticity in gene expression.

Keywords: Feedback regulation; RNA splicing; Stochastic bursting.