JNK activation dynamics drive distinct gene expression patterns over time mediated by mRNA stability

Abstract

c-Jun N-terminal kinase (JNK) plays a major role in the regulation of cell death. Numerous studies have highlighted how the dynamics of this kinase dictate whether cells survive in response to cellular stress or induce cell death mechanisms. However, it is less clear how these dynamics potentially contribute to downstream gene expression patterns through regulated transcription factors like c-Jun. To investigate this question, we used a treatment strategy with the JNK agonist anisomycin to drive specific dynamics; sustained, transient, or pulsed activation, and assessed the impact on downstream gene expression patterns. We observed that multiple gene expression patterns emerged depending on the dynamics of JNK activation. Ordinary Differential Equation (ODE) models suggest that a subset of these clusters are mediated by mRNA stability and supported by measured mRNA decay rates. Specific gene clusters also show enrichment in specific cellular pathways, including cell death and inflammatory signaling, suggesting these dynamics contribute to differential regulation of these pathways. These findings highlight another contribution of JNK dynamics to the regulation of cellular responses to stress stimuli.