The multiscale effects of polycomb mechanisms on 3D chromatin folding

Polycomb group (PcG) proteins silence master regulatory genes required to properly confer cell identity during the development of both Drosophila and mammals. They may act through chromatin compaction and higher-order folding of chromatin inside the cell nucleus. During the last decade, analysis on interphase chromosome architecture discovered self-interacting regions named topologically associated domains (TADs). TADs result from the 3D chromatin folding of a succession of transcribed and repressed epigenomic domains and from loop extrusion mediated by cohesin/CTCF in mammals. Polycomb silenced chromatin constitutes one type of repressed epigenomic domains which form compacted nano-compartments inside cell nuclei. Recruitment of canonical PcG proteins on chromatin relies on initial binding to discrete elements and further spreading into large chromatin domains covered with H3K27me3. Some of these discrete elements have a bivalent nature both in mammals and Drosophila and are dynamically regulated during development. Loops can occur between them, suggesting that their interaction plays both functional and structural roles. Formation of large chromatin domains covered by H3K27me3 seems crucial for PcG silencing and PcG proteins might exert their function through compaction of these domains in both mammals and flies, rather than by directly controlling the nucleosomal accessibility of discrete regulatory elements. In addition, PcG chromatin domains interact over long genomic distances, shaping a higher-order chromatin network. Therefore, PcG silencing might rely on multiscale chromatin folding to maintain cell identity during differentiation.