Cytokine-induced transcriptional memory is evident in the kinetics of transcriptional bursts.

Abstract

During the onset of cytokine-induced transcriptional memory, chromatin-associated proteins, modifications of DNA, and histones act in concert to control gene expression and maintain transcriptional states over several generations. This process is well-exemplified by the transient and amplified expression of pro-inflammatory GBP gene products, which have been shown to exhibit cytokine-induced transcriptional memory under the control of cohesin. However, the effects of transcriptional memory on the transcriptional kinetics of GBP genes remain largely unexplored. Here, we characterize the first-order transcriptional kinetics of GBP5 by modeling ensemble snapshots of nascent and mature RNA transcript counts acquired using fluorescence in-situ hybridization. Our model rigorously infers kinetic parameters for a multi-state model of promoter activation, transcription, and mature RNA nuclear export during cytokine induction, and illustrates the kinetic effects of cytokine-induced transcriptional memory. To perform robust parameter inference and prevent overfitting, we utilize a Sequential Monte Carlo (SMC) algorithm to compute the full posterior distribution on the first-order rate constants. Bayesian model selection reveals modifications to the GBP5 transcriptional state space in HeLa cells primed with interferon-gamma.