Scientists map where Polycomb memory is rebuilt in stem cells

When embryonic stem cells lose a key epigenetic regulator and then regain it, the complex returns to a surprisingly predictable set of genomic addresses, according to a study published in Epigenetics & Chromatin. Researchers engineered an auxin-inducible degradation system in mouse embryonic stem cells that allowed them to reversibly deplete and reintroduce Suz12, a core subunit of Polycomb repressive complex 2, or PRC2. By profiling the genome at an early recovery time point, they identified roughly 1,100 PRC2 nucleation sites characterized by rapid re-accumulation of both Suz12 and the repressive histone mark H3K27me3, with minimal impact on gene expression at those sites.

Polycomb domains help safeguard cell identity by maintaining lineage-specific chromatin states enriched in repressive histone modifications, preserving epigenetic memory of cell lineages. Although PRC2 can reestablish its occupancy after being removed, the mechanisms that direct its earliest recruitment back to specific loci have remained unclear, which is precisely the gap the new system was designed to probe.

The nucleation sites the team mapped were significantly enriched at bivalent promoters, regions that carry both activating and repressive histone marks and are common at genes involved in development. These sites coincided with unmethylated CpG islands and with chromatin states associated with developmental regulation, and they were largely conserved in differentiated cells, suggesting that the targeting logic is not unique to pluripotent stem cells but shared across cell types.

DNA sequence itself appears to contribute to the targeting. Motif analysis of the nucleation sites revealed G/C-rich sequences associated with binding sites for E2F and zinc-finger proteins. Alongside these sequence features, the sites showed strong co-occupancy by MTF2 and JARID2, two PRC2 cofactors previously implicated in Polycomb targeting, pointing to a role for accessory proteins in steering the complex back to its preferred genomic locations.

Chromatin context beyond PRC2 also mattered. H2AK119ub1, a histone mark deposited by Polycomb repressive complex 1, persisted at the nucleation sites even in the absence of PRC2. When the researchers reanalyzed published data, they found a preferential association of canonical PRC1, the Cbx7-containing form of the complex, at these regions. In addition, a subset of nucleation sites overlapped with long-range chromatin interaction anchors, connecting the recruitment process to the three-dimensional organization of the genome.

Taken together, the authors conclude that PRC2 nucleation sites are associated with a combination of chromatin states, DNA sequence features, cofactor co-occupancy, and spatial genome organization, all embedded within a pre-existing canonical-PRC1 context. They propose that this combination of features explains how epigenetic memory can be reestablished through defined genomic and chromatin characteristics rather than through a single dominant mechanism.

Because the work was carried out in mouse embryonic stem cells using an engineered degradation system, the findings describe the behavior of endogenous PRC2 under controlled depletion and reintroduction rather than the response to a natural biological perturbation. The early recovery time point captures the initial phase of re-occupancy, and the authors note that the reported sites showed minimal impact on gene expression during this window. The identification of roughly 1,100 nucleation sites, their overlap with bivalent promoters and CpG islands, and their conservation in differentiated cells together provide a genome-wide map of where Polycomb memory is most readily rebuilt, offering a resource for future studies of how repressive chromatin domains are established and maintained.

Subject of Research: De novo recruitment of the Polycomb repressive complex 2 in mouse embryonic stem cells

Article Title: Mapping early PRC2 nucleation sites upon Suz12 reintroduction reveals features of de novo Polycomb recruitment

Article References: Hernández-Romero, I. A., Peralta-Alvarez, C. A., Román-Figueroa, A., Perez-Molina, R., Cano-Domínguez, N., Soto-Nava, M., Pinta-Castro, F., Garza-Manero, S., Zhou, H., Huang, X., Recillas-Targa, F., Poot-Hernández, A. C., Furlan-Magaril, M., Avila-Rios, S., Valle-Garcia, D., Wang, J., & Valdes, V. J. (2026). Mapping early PRC2 nucleation sites upon Suz12 reintroduction reveals features of de novo Polycomb recruitment. Epigenetics & Chromatin. https://doi.org/10.1186/s13072-026-00695-w

Image Credits: AI Generated

DOI: 10.1186/s13072-026-00695-w

Keywords: PRC2, Suz12, Polycomb, H3K27me3, bivalent promoters, CpG islands, MTF2, JARID2, H2AK119ub1, chromatin, epigenetic memory, mouse embryonic stem cells