Distinct roles for CKM-Mediator in controlling Polycomb-dependent chromosomal interactions and priming genes for induction

Precise control of gene expression underpins normal development. This relies on mechanisms that enable communication between gene promoters and other regulatory elements. In embryonic stem cells (ESCs), the cyclin-dependent kinase module Mediator complex (CKM-Mediator) has been reported to physically link gene regulatory elements to enable gene expression and also prime genes for induction during differentiation. Here, we show that CKM-Mediator contributes little to three-dimensional genome organization in ESCs, but it has a specific and essential role in controlling interactions between inactive gene regulatory elements bound by Polycomb repressive complexes (PRCs). These interactions are established by the canonical PRC1 (cPRC1) complex but rely on CKM-Mediator, which facilitates binding of cPRC1 to its target sites. Importantly, through separation-of-function experiments, we reveal that this collaboration between CKM-Mediator and cPRC1 in creating long-range interactions does not function to prime genes for induction during differentiation. Instead, we discover that priming relies on an interaction-independent mechanism whereby the CKM supports core Mediator engagement with gene promoters during differentiation to enable gene activation.

Automated summary

Precise control of gene expression during development is crucial, and CKM-Mediator plays a critical role in this process. It establishes physical links between gene regulatory elements and enables gene expression and priming for induction in embryonic stem cells. CKM-Mediator is specifically involved in controlling interactions between inactive gene regulatory elements bound by PRCs, and it facilitates the binding of PRC1 to its target sites. Interestingly, CKM-Mediator and PRC1 collaboration in creating long-range interactions does not contribute to gene priming during differentiation, but rather gene activation relies on an interaction-independent mechanism where CKM supports core Mediator engagement with gene promoters.