Schematic representation of predicted functions of the pPIWI-RE and MedPIWI domains. (A) pPIWI-RE domain associates with DNA-RNA hybrid structure present during R-loop formation in an invasive DNA element, resulting in recruitment of the DinG helicase and endoDNAse REase domains. (B) Regulation of the core Mediator complex via the CDK8 subcomplex is depicted, beginning at left with 1) simplified representation of the PIC, poised for initiation of transcription. 2) In absence of CDK8 subcomplex, the core Mediator complex recruits pol II and transcription is initiated. 3) Kinase activity-independent repression of transcription: the CDK8 subcomplex (depicted as yellow oval) transiently associates with core Mediator complexes across the genome ; availability of a small RNA binding substrate for the MedPIWI domain in the Med13 component of the CDK8 subcomplex triggers a shift from transient association to repressive role of CDK8 subcomplex, triggering a conformational switch in the Mediator-CDK8 combined complex which blocks pol II re-association. 4) lncRNA-mediated transcriptional activation: association of Med12 with activating lncRNA transcribed and looping from distal enhancer element (depicted as box colored in green) facilitates CDK8 kinase-mediated phosphorylation of transcriptional-activating histone H3 serine 10, resulting in association of pol II and transcriptional activation . 5) Additional layers of CDK8 subcomplex-mediated transcriptional repression: CDK8 kinase phosphorylates TFIIH  or C-terminal tail of pol II  and Med12-mediated recruitment of SET domain methyltransferase (G9a) methylates histone H3 lysine 9 , all resulting in repression of transcription. Abbreviations: P, phosphorylation event; Me, methylation event; S, switch resulting in conformational change.