CommentPublished: 11 September 2026Chen Davidovich ORCID: orcid.org/0000-0002-1085-60941,2 Nature Reviews Molecular Cell Biology (2026) Cite this articleSave articleView saved researchFour recent studies applied different bioinformatics pipelines to the same dataset to address a controversial question: does the PRC2 complex bind RNA inside cells? Here, I argue that none of these studies conclusively answers this question, but collectively, they offer technical insights into the pitfalls of settling this debate.This is a preview of subscription content, access via your institutionAccess options Access through your institutionAccess Nature and 54 other Nature Portfolio journalsGet Nature+, our best-value online-access subscription27,99 € / 30 dayscancel any timeLearn moreSubscribe to this journalReceive 12 print issues and online access269,00 € per yearonly 22,42 € per issueLearn moreBuy this articlePurchase on SpringerLinkInstant access to the full article PDF.39,95 €Prices may be subject to local taxes which are calculated during checkoutSubjectsGene silencingHistone post-translational modificationsLong non-coding RNAsReferencesRinn, J. L. et al. Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Cell 129, 1311–1323 (2007).Article CAS PubMed PubMed Central Google Scholar Davidovich, C. & Cech, T. R. The recruitment of chromatin modifiers by long noncoding RNAs: lessons from PRC2. RNA 21, 2007–2022 (2015).Article CAS PubMed PubMed Central Google Scholar Cech, T. R. at al. PRC2–RNA interactions: Viewpoint from Tom Cech, Chen Davidovich, and Richard Jenner. Mol. Cell 84, 3593–3595 (2024).Article CAS PubMed Google Scholar Guo, J. K. at al. PRC2–RNA interactions: Viewpoint from Jimmy K. Guo, Mario R. Blanco, and Mitchell Guttman. Mol. Cell 84, 3578–3585 (2024).Article CAS PubMed Google Scholar Lee, Y. & Lee, J. T. PRC2-RNA interactions: Viewpoint from YongWoo Lee and Jeannie T. Lee. Mol. Cell 84, 3586–3592 (2024).Article CAS PubMed Google Scholar Lewis, E. B. A gene complex controlling segmentation in Drosophila. Nature 276, 565–570 (1978).Article CAS PubMed Google Scholar Cao, R. et al. Role of histone H3 lysine 27 methylation in Polycomb-group silencing. Science 298, 1039–1043 (2002).Article CAS PubMed Google Scholar Guo, J. K. et al. Denaturing purifications demonstrate that PRC2 and other widely reported chromatin proteins do not appear to bind directly to RNA in vivo. Mol. Cell 84, 1271–1289 (2024).Article CAS PubMed PubMed Central Google Scholar Henderson, S. et al. Denaturing purifications support direct interaction between PRC2 and RNA in cells. Preprint at bioRxiv https://doi.org/10.64898/2026.05.19.725914 (2026).Lee, Y. et al. Re-analysis of CLAP supports prior evidence of PRC2 as an RNA binding protein. Patterns 7, 101641 (2026).Article Google Scholar Guo, J. K. at al. Failing to account for RNA quantity inflates background and leads to the misleading appearance that PRC2 and GFP bind to RNA in vivo. Preprint at bioRxiv https://doi.org/10.1101/2024.11.02.621417 (2024).Trotman, J. B. et al. Isogenic comparison of Airn and Xist reveals core principles of Polycomb recruitment by lncRNAs. Mol. Cell 85, 1117–1133 (2025).Article CAS PubMed PubMed Central Google Scholar Cheng, Q.-X. et al. Co-profiling of in situ RNA-protein interactions and transcriptome in single cells and tissues. Nat. Methods 22, 1824–1835 (2025).Article CAS PubMed PubMed Central Google Scholar Steegen, S. at al. Increasing transparency through a multiverse analysis. Perspect. Psychol. Sci. J. Assoc. Psychol. Sci. 11, 702–712 (2016).Article Google Scholar Song, J. et al. RNA-induced PRC2 inhibition depends on the sequence of bound RNA. Nat. Commun. https://doi.org/10.1038/s41467-026-72294-y (2026).Article PubMed PubMed Central Google Scholar Download referencesAuthor informationAuthors and AffiliationsDepartment of Biochemistry and Molecular Biology, Biomedicine Discovery Institute, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Victoria, AustraliaChen DavidovichRNA Mass Spectrometry Platform, Monash Proteomics and Metabolomics Platform, Monash University, Clayton, Victoria, AustraliaChen DavidovichAuthorsChen DavidovichView author publicationsSearch author on:PubMed Google ScholarCorresponding authorCorrespondence to Chen Davidovich.Ethics declarationsCompeting interestsThe author declares no competing interests.Peer reviewPeer review informationNature Reviews Molecular Cell Biology thanks Igor Ulitsky and the other, anonymous,reviewer(s) for their contribution to the peer review of this work.Supplementary informationRights and permissionsReprints and permissionsAbout this article