CDK8 and CDK19 act redundantly to control the CFTR pathway in the intestinal epithelium

CDK8 and CDK19 form a conserved cyclin-dependent kinase subfamily that interacts with the essential transcription complex, Mediator, and also phosphorylates the C-terminal domain of RNA polymerase II. Cells lacking either CDK8 or CDK19 are viable and have limited transcriptional alterations, but whether the two kinases redundantly control cell proliferation and differentiation is unknown. Here, we find in mice that CDK8 is dispensable for regulation of gene expression, normal intestinal homeostasis, and efficient tumourigenesis, and is largely redundant with CDK19 in the control of gene expression. Their combined deletion in intestinal organoids reduces long-term proliferative capacity but is not lethal and allows differentiation. However, double-mutant organoids show mucus accumulation and increased secretion by goblet cells, as well as downregulation of expression of the cystic fibrosis transmembrane conductance regulator (CFTR) and functionality of the CFTR pathway. Pharmacological inhibition of CDK8/19 kinase activity in organoids and in mice recapitulates several of these phenotypes. Thus, the Mediator kinases are not essential for cell proliferation and differentiation in an adult tissue, but they cooperate to regulate specific transcriptional programmes.

Automated summary

CDK8 and CDK19 are conserved cyclin-dependent kinase subfamily members that interact with Mediator and phosphorylate RNA polymerase II. Deletion of either CDK8 or CDK19 in mice does not significantly affect gene expression or normal intestinal homeostasis, but simultaneous deletion of both kinases reduces long-term proliferative capacity and results in mucus accumulation and increased secretion by goblet cells. Furthermore, CDK8 and CDK19 cooperatively regulate specific transcriptional programs, as shown by the downregulation of CFTR expression and CFTR pathway functionality observed in double-mutant organoids. Pharmacological inhibition of CDK8/19 kinase activity recapitulates several of these phenotypes.