Genetically Engineered Mice Unveil In Vivo Roles of the Mediator Complex

Abstract

The Mediator complex is a multi-subunit protein complex which plays a significant role in the regulation of eukaryotic gene transcription. It provides a platform for the interaction of transcriptional factors and RNA polymerase II, thus coupling external and internal stimuli with transcriptional programs. Molecular mechanisms underlying Mediator functioning are intensively studied, although most often using simple models such as tumor cell lines and yeast. Transgenic mouse models are required to study the role of Mediator components in physiological processes, disease, and development. As constitutive knockouts of most of the Mediator protein coding genes are embryonically lethal, conditional knockouts and corresponding activator strains are needed for these studies. Recently, they have become more easily available with the development of modern genetic engineering techniques. Here, we review existing mouse models for studying the Mediator, and data obtained in corresponding experiments.

Knockout of cyclin dependent kinases 8 and 19 leads to depletion of cyclin C and suppresses spermatogenesis and male fertility in mice

“…Despite that, the knockout of Cdk8 is only critical in embryogenesis (Westerling et al, 2007), with no phenotype in adult organisms (McCleland et al, 2015), while Cdk19 is wholly dispensable. The same tendency is observed for the knockout of MED subunits and other CKM proteins: constitutive KOs are often embryonically lethal (except for paralog of MED12 - MED12L), while tissue-specific knockouts in adult animals rarely have a severe phenotype (Ilchuk et al, 2023).…”

“…Mice with Med1 fl/fl /Vasa-Cre tissue specific KO had an opposite phenotype to the one described here: prophase I passage was accelerated in these mice and spermatocytes entered zygotene/pachytene stage prematurely [51]. The difference between these effects is quite interesting in the context of the concept that association with CKM attenuates Mediator-dependent transcription either by sterically preventing TF binding [52], or by post-transcriptional regulation of Mediator complex subunits [5,53]. As far as we know, besides the current work [51], is the only paper establishing a connection between any components of the Mediator complex and spermatogenesis.…”

“…We demonstrated a disruption of steroid biosynthesis in Leydig cells which could play the key role for the observed phenotype. A number of works (reviewed in (Ilchuk et al, 2023)) affirm a significant role of Mediator complex in lipid metabolism and biosynthesis as one of the main cofactors for main adipogenic TFs such as C/EBPα, PPARγ and SREBP.…”