Chromatin folding and nuclear architecture: PRC1 function in 3D

Abstract

Embryonic development requires the intricate balance between the expansion and specialisation of defined cell types in time and space. The gene expression programmes that underpin this balance are regulated, in part, by modulating the chemical and structural state of chromatin. Polycomb repressive complexes (PRCs), a family of essential developmental regulators, operate at this level to stabilise or perpetuate a repressed but transcriptionally poised chromatin configuration. This dynamic state is required to control the timely initiation of productive gene transcription during embryonic development. The two major PRCs cooperate to target the genome, but it is PRC1 that appears to be the primary effector that controls gene expression. In this review I will discuss recent findings relating to how PRC1 alters chromatin accessibility, folding and global 3D nuclear organisation to control gene transcription.

Figure 1

PRC1 composition and the regulation of chromatin structure. Polycomb Repressive Complex 1 (PRC1) comprises a core assembly of the E3 ubiquitin-ligase RING1A or B and one of six PCGF proteins. PRC1 can be stratified into functionally distinct subgroups based on the association of the core heteroduplex with additional subunits. Canonical PRC1s (cPRC1; upper left panel) contain a CBX and PHC component associated with either of PCGF2/MEL18 or PCGF4/BMI1. These complexes function primarily at the level of chromatin structure, either by anchoring DNA loops through the head-to-tail association of the SAM domain of PHC (upper right panel), or through local nucleosomal compaction mediated by the positively charged IDR of CBX2 (lower right panel). In contrast non-canonical PRC1s (ncPRC1s) associate with either RYBP or YAF2 and one of PCGF1, 3, 5 or 6. ncPRC1s are the primary drivers of H2AK119ub1 deposition due to enhanced RING1A/B by RYBP or YAF2 (lower left panel).

Figure 2

Phase separation and the architecture of polycomb bodies. Microscopically visible foci containing high local concentrations of polycomb proteins and their target genes have been identified in the nuclei of both mammals and flies. These membraneless organelles, known as polycomb bodies (represented as yellow foci), range in size from 10s to 100s nm, and form through interactions facilitated by cPRC1 subunits. PHCs oligomerise through head-to-tail interactions between their SAM domains and drive the formation of PRC1-chains that can bridge DNA fibers into loop-like structures (‘DNA Looping’; upper-right inset). The intrinsically disordered region (IDR) of CBX2 provides a positively charged interface that facilitates electrostatic interactions between polycomb subunits and potentially other constituents of polycomb bodies (e.g. DNA/RNA; lower-right inset). cPRC1 mediated looping and chromatin compaction are therefore tightly associated with the formation of a liquid-like phase separated repressive nuclear compartment. Mutations which disrupt both PRC1-mediated chromatin topology and nuclear clustering lead to the transcriptional upregulation of PRC1-target genes.