Mediator kinase inhibition drives myometrial stem cell differentiation and the uterine fibroid phenotype through super-enhancer reprogramming [RNA-seq]

Although it is known that the uterine fibroid linked MED12 mutations disrupt the CDK8/19 kinase activity, how CDK8/19 disruption contributes to making the myometrial stem cell tumorigenic and form uterine fibroids. This study seeks to determine the molecular consequences of pharmacologically disrupting mediator kinase activity in myometrial stem cells, the presumptive cell of origin for uterine fibroids, through parallel transcriptomic and epigenomic profiling by bulk RNA-seq and H3K27ac CUT&RUN. Overall design: We treated myometrial stem cells with CDK8/19 inhibitor CCT251545 (treatment) or DMSO (control) at two timepoints and processed the treated cells for bulk mRNA sequencing and enhancer profiling by H3K27ac CUT&RUN in parallel at each timepoints.