Abstract
A major unsolved problem in epigenetics is how RNA regulates Polycomb repressive complex 2 (PRC2), a complex that trimethylates histone H3 Lys27 (H3K27me3) to form repressive chromatin. Key questions include how PRC2 binds RNA in vivo and what the functional consequences of binding are. In this Perspective, we expound on the viewpoint that RNA is integral to the stepwise regulation of PRC2 activity. Using the long non-coding RNA XIST and X chromosome inactivation as a model, we discuss evidence indicating that RNA is involved in PRC2 recruitment onto chromatin, in induction of its catalytic activity and in its eviction from chromatin. Studies have also implicated RNA in controlling promoter-proximal pausing of RNA polymerase II. The cumulative data argue that the functional consequences of PRC2–RNA interactions crucially depend on RNA conformation. We recognize that alternative hypotheses exist and therefore we attempt to integrate contrary data. Thus, although an RNA-rich landscape is emerging for Polycomb complexes, additional work is required to resolve a broad range of data interpretations.
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Acknowledgements
The authors acknowledge funding from the Pew Charitable Trust (the Latin American Fellowship), from ANID FONDECYT Regular (grant 1240853) and Nucleo UNAB (grant DI-03-22/NUC to R.A.) and a grant from the National Institutes of Health (grant R01HD097665 to J.T.L.). We thank Y. W. Lee, P. Das, B. Kesner and R. Blum for their valuable discussions.
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R.A., M.R. and J.T.L. researched data for the article. All authors contributed substantially to the discussion of the content. R.A., M.R. and J.T.L. wrote the article. V.L. drafted the original figures. All authors reviewed and edited the manuscript before submission.
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J.T.L. is a cofounder of Fulcrum Therapeutics, a scientific advisor to Skyhawk Therapeutics, and a non-executive director of GlaxoSmithKline.
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Aguilar, R., Rosenberg, M., Levy, V. et al. An evolving landscape of PRC2–RNA interactions in chromatin regulation. Nat Rev Mol Cell Biol 26, 631–642 (2025). https://doi.org/10.1038/s41580-025-00850-3
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DOI: https://doi.org/10.1038/s41580-025-00850-3
