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

Area of Science:

• Cellular Biology
• Molecular Biology
• Systems Biology

Background:

• c-Jun N-terminal kinase (JNK) is crucial for regulating cell death.
• JNK dynamics influence cell survival versus cell death decisions under stress.
• The link between JNK dynamics and downstream gene expression via transcription factors like c-Jun requires further investigation.

Purpose of the Study:

• To investigate how specific JNK activation dynamics (sustained, transient, pulsed) affect downstream gene expression patterns.
• To explore the role of mRNA stability in mediating gene expression responses to JNK dynamics.
• To identify cellular pathways differentially regulated by JNK dynamics.

Main Methods:

• Utilized anisomycin, a JNK agonist, to induce distinct JNK activation dynamics in cells.
• Assessed downstream gene expression patterns resulting from these dynamics.
• Employed Ordinary Differential Equation (ODE) models and measured mRNA decay rates to analyze gene expression regulation.
• Performed pathway enrichment analysis on identified gene clusters.

Main Results:

• Distinct gene expression patterns were observed, contingent upon the specific dynamics of JNK activation.
• ODE models indicated that mRNA stability mediates a subset of these gene expression clusters.
• Measured mRNA decay rates supported the role of mRNA stability.
• Specific gene clusters were enriched in cell death and inflammatory signaling pathways.

Conclusions:

• JNK activation dynamics significantly shape downstream gene expression patterns.
• mRNA stability is a key mechanism influencing gene expression responses to JNK signaling.
• JNK dynamics contribute to the differential regulation of critical cellular pathways, including cell death and inflammation.
• These findings add to the understanding of how JNK signaling controls cellular responses to stress.