In the crowded nucleus of every human cell, the two-metre stretch of DNA in each chromosome is constantly being read, folded and annotated by armies of protein complexes. Among the most consequential of these architects are the Polycomb group proteins, master regulators that lock genes into silent states and, in doing so, help decide what kind of cell a stem cell will ultimately become. Now, a study published in Nature Structural & Molecular Biology by Ciapponi and colleagues has delivered the most complete structural portrait to date of canonical Polycomb repressive complex 1, better known as canonical PRC1, using cryo-electron microscopy to reveal how this multi-subunit machine assembles, how it chemically modifies chromatin, and how it is steered to the right places in the genome. The findings, reported online on 14 September 2026, address questions that chromatin biologists have wrestled with for decades.
Polycomb repressive complexes were first discovered in fruit flies through mutations that transformed body segments, a striking phenotype that hinted at their role in maintaining the expression patterns of developmental genes. In mammals, the two major Polycomb systems, PRC1 and PRC2, work in concert to silence lineages-inappropriate genes. PRC2 deposits the histone mark H3K27me3, a chemical flag on lysine 27 of histone H3, while PRC1 deposits a complementary mark, monoubiquitinated lysine 119 on histone H2A, abbreviated H2AK119ub. Both marks are hallmarks of facultative heterochromatin, the compacted but still potentially reversible form of chromatin that keeps developmental regulators quiet without permanently altering the underlying DNA sequence.
Canonical PRC1 is not a single protein but a holocomplex built from four families of subunits. At its catalytic heart sits a heterodimer of a RING-family E3 ubiquitin ligase component, RING1A or RING1B, paired with one of six PCGF proteins, most commonly PCGF2 or PCGF4 in the canonical form. Surrounding this catalytic core are the Polyhomeotic proteins PHC1, PHC2 or PHC3, which mediate higher-order chromatin interactions, and the chromodomain proteins of the CBX family, CBX2, CBX4, CBX6, CBX7 or CBX8, which read the H3K27me3 mark laid down by PRC2 and help recruit PRC1 to its genomic destinations. This modular organisation has made PRC1 notoriously difficult to study as an intact entity: the complex flexes, adopts multiple compositions, and interacts dynamically with its nucleosome substrate.
Cryo-electron microscopy is uniquely suited to this challenge. The technique flash-freezes purified protein complexes in a thin film of vitreous ice and images thousands of individual particles, computationally sorting the views into a three-dimensional map at near-atomic resolution. For PRC1, the technical hurdles were formidable. The complex must be purified in a homogeneous state, yet its different subunit paralogs generate compositional heterogeneity that can blur reconstructions. By isolating a defined canonical holocomplex and pushing the limits of particle classification and map refinement, Ciapponi and colleagues were able to visualise the architecture of the entire assembly, resolving how each subunit docks onto its neighbours and where the catalytic machinery sits relative to the rest of the complex.
The resulting structure reveals a striking spatial economy. The RING1 catalytic subunit and its PCGF partner form a central scaffold onto which the Polyhomeotic and CBX subunits assemble in a defined arrangement. Critically, the positions of these accessory modules explain why they are not passive passengers. The chromodomain subunit projects away from the catalytic core, positioned to reach out and engage neighbouring nucleosomes bearing the H3K27me3 mark, thereby coupling recognition of the PRC2 histone code to the placement of the PRC1 ligase. The Polyhomeotic subunits, meanwhile, occupy an architecture consistent with their established role in bridging distant chromatin regions, the process of chromatin compaction that physically reinforces gene silencing.
Beyond the static snapshot, the study directly interrogated enzymatic function. The catalytic RING1B-containing core acts as an E3 ubiquitin ligase, transferring ubiquitin from an E2 conjugating enzyme onto lysine 119 of histone H2A within the nucleosome. In experiments with reconstituted nucleosomes and purified complex variants, the authors examined how mutations or perturbations that disrupt the interfaces seen in the structure affect H2A monoubiquitination activity. The results support a model in which the holocomplex architecture coordinates substrate engagement: the catalytic module must be correctly positioned relative to the nucleosome acidic patch, the docking surface on the histone disc where RING1B binds, while the peripheral subunits stabilise the active conformation and mediate the multivalent contacts that make targeting efficient.
Perhaps the most consequential aspect of the work concerns genome targeting. How does PRC1 find the hundreds of genomic loci it represses, including the CpG islands that overlap promoters of developmental regulators? The prevailing model holds that recruitment depends on combinatorial recognition: CBX chromodomains bind H3K27me3 deposited by PRC2, while additional factors recognise unmethylated CpG DNA. The new structure shows how the CBX subunit is oriented within the holocomplex such that its chromodomain can sample adjacent nucleosomes, and how the overall geometry of the complex allows multiple weak interactions to cooperate into a stable, specific engagement with its chromatin substrate. This multivalent design explains how PRC1 achieves both specificity, favouring the correct genomic loci, and stability, maintaining silencing through cell divisions.
The biological stakes of this work are considerable. Aberrant Polycomb function is implicated in a long list of human diseases. Overexpression of BMI1, the mammalian homolog of PCGF4, drives proliferation in numerous cancers and is a recognised marker of tumour-initiating stem-like cells. Loss-of-function mutations in Polycomb components cause developmental syndromes, including Weaver syndrome and other overgrowth disorders linked to EZH2 and EED of PRC2, and Shashi-Penman syndrome linked to EED and EZHIP, while somatic alterations in PRC1 genes recur across lymphoma, leukaemia and solid tumours. Understanding the assembly pathway and enzymatic mechanism of canonical PRC1 at structural resolution therefore provides a rational foundation for therapeutic intervention, informing the design of molecules that destabilise pathological complexes or block their catalytic activity.
The study also resolves longstanding debates about the relationship between structure and function in Polycomb biology. Earlier biochemical work established the individual interactions, RING1B with PCGF subunits, CBX chromodomains with H3K27me3, Polyhomeotic with chromatin, but it remained unclear how these pieces fit together in the intact holocomplex and whether the intact assembly behaves differently from its parts. By presenting the architecture of the canonical PRC1 holocomplex alongside enzymatic assays and genome-targeting data within a single integrated analysis, Ciapponi and colleagues provide the kind of mechanistic completeness that individual fragment studies could not. Their structure serves as a framework onto which decades of genetic, biochemical and genomic observations can now be mapped.
Future work will build on this foundation in several directions. Cryo-EM structures of PRC1 variants containing different PCGF, CBX and Polyhomeotic paralogs will reveal how compositional diversity translates into functional specialisation. Higher-resolution reconstructions of the complex bound to nucleosome substrates will clarify the exact geometry of ubiquitin transfer onto H2A lysine 119. And comparative studies with the non-canonical PRC1 complexes, which lack CBX subunits and rely instead on KDM2B and other recruitment factors, will illuminate how evolution has tuned the same catalytic core to serve distinct targeting strategies. For now, the structure determined by Ciapponi and colleagues stands as a landmark: the first comprehensive view of one of the cell’s most important gene-silencing machines, and a vivid demonstration of how cryo-electron microscopy is transforming our understanding of the molecular logic of chromatin regulation.
Subject of Research: Cryo-EM structure, enzymatic activity and genome targeting of canonical Polycomb repressive complex 1
Article Title: Cryo-EM structure, enzymatic activity and genome targeting of canonical PRC1
Article References: Cryo-EM structure, enzymatic activity and genome targeting of canonical PRC1. (n.d.). https://doi.org/10.1038/s41594-026-01885-6
Image Credits: AI Generated
DOI: 10.1038/s41594-026-01885-6
Keywords: PRC1, cryo-EM, Polycomb, chromatin, epigenetics, gene silencing, H2A ubiquitination, RING1B, structural biology, histone modification, genome targeting, structure
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Juliet Wilcox. (September 21, 2026). Cryo-EM Reveals How Polycomb Repressive Complex 1 Assembles, Works and Finds Its Targets. Scienmag. https://scienmag.com/cryo-em-reveals-how-polycomb-repressive-complex-1-assembles-works-and-finds-its-targets/
Juliet Wilcox. “Cryo-EM Reveals How Polycomb Repressive Complex 1 Assembles, Works and Finds Its Targets.” Scienmag, 21 September 2026, https://scienmag.com/cryo-em-reveals-how-polycomb-repressive-complex-1-assembles-works-and-finds-its-targets/. Accessed 21 September 2026.
Juliet Wilcox. “Cryo-EM Reveals How Polycomb Repressive Complex 1 Assembles, Works and Finds Its Targets.” Scienmag. September 21, 2026. https://scienmag.com/cryo-em-reveals-how-polycomb-repressive-complex-1-assembles-works-and-finds-its-targets/
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Tags: chromatincryo-EMepigeneticsgene silencinggenome targetingH2A ubiquitinationhistone modificationPolycombPRC1RING1Bstructural biologystructure
