Mediator Roles Going Beyond Transcription.

Dysfunctions of nuclear processes including transcription and DNA repair lead to severe human diseases. Gaining an understanding of how these processes operate in the crowded context of chromatin can be particularly challenging. Mediator is a large multiprotein complex conserved in eukaryotes with a key coactivator role in the regulation of RNA polymerase (Pol) II transcription. Despite intensive studies, the molecular mechanisms underlying Mediator function remain to be fully understood. Novel findings have provided insights into the relationship between Mediator and chromatin architecture, revealed its role in connecting transcription with DNA repair and proposed an emerging mechanism of phase separation involving Mediator condensates. Recent developments in the field suggest multiple functions of Mediator going beyond transcriptional processes per se that would explain its involvement in various human pathologies.

Functional interplay between Mediator and RSC chromatin remodeling complex controls nucleosome-depleted region maintenance at promoters.

Chromatin organization is crucial for transcriptional regulation in eukaryotes. Mediator is an essential and conserved co-activator thought to act in concert with chromatin regulators. However, it remains largely unknown how their functions are coordinated. Here, we provide evidence in the yeast Saccharomyces cerevisiae that Mediator establishes physical contact with RSC (Remodels the Structure of Chromatin), a conserved and essential chromatin remodeling complex that is crucial for nucleosome-depleted region (NDR) formation. We determine the role of Mediator-RSC interaction in their chromatin binding, nucleosome occupancy, and transcription on a genomic scale. Mediator and RSC co-localize on wide NDRs of promoter regions, and specific Mediator mutations affect nucleosome eviction and TSS-associated +1 nucleosome stability. This work shows that Mediator contributes to RSC remodeling function to shape NDRs and maintain chromatin organization on promoter regions. It will help in our understanding of transcriptional regulation in the chromatin context relevant for severe diseases.