Functions of Cyclin C and Cyclin-Dependent Kinases 8 and 19 (CDK8/19) in the immune system

Cyclin-dependent kinases (CDKs) constitute a family of serine/threonine kinases that play essential roles in regulating cellular proliferation, differentiation, and homeostasis. While classical CDKs primarily control cell cycle progression, a distinct subset of transcription-associated CDKs, including CDK8 and CDK19 together with their activating partner cyclin C, modulates gene expression through regulation of the Mediator complex and phosphorylation of transcriptional regulators. Despite extensive in vitro and cancer-focused studies, the physiological functions of cyclin C–CDK8/19 in vivo remain incompletely understood.
This thesis investigates the roles of cyclin C–CDK8/19 in immune cell development and function using genetically engineered mouse models. By selectively disrupting components of the cyclin C–CDK8/19 module in hematopoietic and immune cell lineages, this work examines how transcriptional CDKs contribute to immune cell differentiation, lineage specification, and functional maturation. The findings demonstrate that cyclin C–CDK8/19 activity is required for normal macrophage differentiation and immune homeostasis, highlighting context-dependent transcriptional roles distinct from those of cell cycle-associated CDKs.
In parallel, this thesis explores the role of CDK1 beyond its canonical function in cell cycle control, focusing on its involvement in epigenetic regulation in embryonic stem cells. Using chemical-genetic approaches combined with quantitative phosphoproteomics, chromatin immunoprecipitation, and transcriptional profiling, this work identifies CDK1-dependent phosphorylation events on chromatin-associated regulators and links CDK1 activity to modulation of histone modifications and transcriptional programs associated with pluripotency and differentiation.
Together, these studies expand the functional landscape of CDKs by demonstrating that transcriptional and cell cycle CDKs exert critical regulatory roles beyond proliferation control. The work presented in this thesis underscores the importance of CDK-mediated transcriptional and epigenetic regulation in immune cell physiology and early developmental contexts, providing insights with potential relevance for inflammatory disease, cancer, and therapeutic targeting of CDK pathways.