Cyclin C Regulated Transcriptional Response to Stress

Abstract

When cells are exposed to extracellular stress, there is a coordinated shift in cellular and molecular actions that determine the fate of the cell. An important aspect of this response involves transcriptional reprogramming to either mitigate the effects of the stress or commit to a cell death pathway. This altered transcriptome causes disruption of normal cellular functions, such as growth and proliferation. It also promotes the transcription of genes involved in stress response and cell death. Our previous findings from RNA sequencing (RNA‐seq) studies has shown that the conserved transcription factor, cyclin C, regulates the stress responsive transcriptome in mouse embryonic fibroblast (MEF) cells. Cyclin C is a member of the Cdk8‐kinase module (CKM) which, depending on the locus, can function to either induce or repress transcription. The genes induced by cyclin C prior to stress include those that promote growth and proliferation. In contrast, the genes repressed by cyclin C prior to stress include those that promote autophagy and apoptosis. After exposure to stress, the role of cyclin C is disrupted on each group of genes. This transcriptional reprogramming event results in the repression of the growth and proliferation genes, and induction of the autophagy and apoptosis genes. In the present study, chromatin immunoprecipitation (ChIP) studies show that cyclin C is associated with the promoter region of genes identified through RNA‐seq analysis. ChIP was used to determine promoter occupancy by cyclin C and transcriptional changes occurring from exposure to either oxidative stress or Torin1 to induce apoptosis and autophagy, respectively. Stressed cells show significantly reduced, or complete loss of cyclin C occupancy at specific genes. Cyclin C is also recruited to the promoter of other genes following exposure to stress to induce transcription. The genes identified in this study are involved in the cellular responses upon exposure to stress; specifically, the repression of growth and proliferation and the induction of autophagy and apoptosis. These findings demonstrate a direct role for cyclin C in the transcriptional changes occurring following exposure to stress, and subsequently contribution to cell fate determination.