Yanhui Xu's research team reveals the molecular mechanism of PIC-Mediator organization on chromatin and underscores the significance of the +1 nucleosome in regulating transcription initiation.Their paper entitled Structures of +1 nucleosome–bound PIC-Mediator complex published online at the Science on 6 October 2022.

Eukaryotic transcription is regulated by the chromatin architecture around the core promoter, which is established by combinatory factors including DNA sequence, transcription factors, and chromatin remodelers. The +1 nucleosome is thought to be a barrier of Pol II–mediated early elongation and a transcription regulator containing characteristic epigenetic marks including H2A.Z and H3.3 histone variants and histone acetylation and H3K4 trimethylation (H3K4me3). The +1 nucleosome is positioned ~40 bp downstream of TSS, and PIC may also regulate the dynamics of the +1 nucleosome, suggesting a functional connection between PIC and the +1 nucleosome in a position-dependent manner. Despite the known critical roles of the +1 nucleosome in transcription regulation, its intimate binding to transcription machineries was neither structurally visualized nor previously expected.

In this study, Yanhui Xu’s research team determined the structures of nucleosome-bound PIC-Mediator. Structural and biochemical analyses show that the nucleosome makes multiple contacts with PIC-Mediator and may enhance transcription activity if the nucleosome is positioned 40 or 50 base pairs (but not 70 base pairs) downstream of TSS. In summary, the +1 nucleosome not only exists as a barrier that should be overcome during early transcription elongation, but it also serves as a hub organizing and modulating the PIC-Mediator complex on chromatin.This study provides a structural basis for understanding the regulatory function of the +1 nucleosome in transcription initiation.

Schematic model of PIC-Mediator organization on chromatin(Chen et al., Science 378, 62-68).