Abstract
Polycomb repressive complex 2 (PRC2) mediates developmental gene repression as two classes of holocomplexes, PRC2.1 and PRC2.2. EPOP is an accessory subunit specific to PRC2.1, which also contains PCL proteins. Unlike other accessory subunits that collectively facilitate PRC2 targeting, EPOP was implicated in an enigmatic inhibitory role, together with its interactor Elongin BC. We report an unusual molecular mechanism whereby EPOP regulates PRC2.1 by directly modulating its oligomerization state. EPOP disrupts the PRC2.1 dimer and weakens its chromatin association, likely by disabling the avidity effect conferred by the dimeric complex. Congruently, an EPOP mutant specifically defective in PRC2 binding enhances genome-wide enrichments of MTF2 in mouse epiblast-like cells. Elongin BC is largely dispensable for the EPOP-mediated inhibition of PRC2.1. EPOP defines a distinct subclass of PRC2.1, which may uniquely maintain an epigenetic program by preventing the over-repression of key gene regulators along the continuum of early differentiation.
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Data availability
The crystal structure described in this work has been deposited in the Protein Data Bank (PDB) under the accession number 9XZI. Genomics data have been deposited in NCBI’s Gene Expression Omnibus under the accession numbers GSE264672 and GSE264673. LC-MS/MS data files have been deposited to the ProteomeXchange via the MassIVE partner repository with the accession code PXD072233. Source data are provided in this paper.
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Acknowledgements
The cDNA of EPOP was kindly provided by Dr. Robert Liefke and Dr. Yang Shi. The cDNAs of human PRC2 core subunits were kindly provided by Dr. Robert Kingston. This research was supported by NIH grants R35GM136308 and R21NS137323 to X.L. X.L. is a W.W. Caruth, Jr., Scholar in Biomedical Research. L.G. was supported by an American Heart Association postdoctoral fellowship 19POST34450043, the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB1230000), NSFC-Joint Foundation of Yunnan Province (U24A20806), Introducing Talents Start-up Fund of Kunming Institute of Botany, Chinese Academy of Sciences (51E46G0111K1), and Fund of State Key Laboratory of Phytochemistry and Natural Medicines (52E46P5211Z1). S.C. was supported by the National Natural Science Foundation of China grant 32100464. Some data presented in this report were acquired with a mass photometer that was supported by an award S10OD030312-01 from the NIH. Results shown in this report are derived from work performed at Argonne National Laboratory, Structural Biology Center (SBC) at the Advanced Photon Source. SBC-CAT is operated by UChicago Argonne, LLC, for the U.S. Department of Energy, Office of Biological and Environmental Research under contract DE-AC02-06CH11357. Use of the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the National Institutes of Health, National Institute of General Medical Sciences (P30GM133894). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.
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Xin.L. conceived the study; L.G., Xiuli.L., M.Y.B, X.Y., S.C., and Xin.L. designed and performed the experiments; X.Y. and Xin.L. analyzed the structural data; Xiuli.L., Z.Y., C.X., and Xin.L. analyzed the genomics data; A.L. analyzed the proteomics data; L.G., Xiuli.L., X.Y., Z.Y., C.X., and Xin.L. wrote the manuscript.
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Gong, L., Liu, X., Yang, X. et al. EPOP restricts PRC2.1 targeting to chromatin by directly modulating enzyme complex dimerization. Nat Commun (2026). https://doi.org/10.1038/s41467-025-68280-5
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DOI: https://doi.org/10.1038/s41467-025-68280-5
