{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:30:07Z","timestamp":1786339807019,"version":"build-2736575974"},"reference-count":46,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":6,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100014188","name":"MSIT","doi-asserted-by":"publisher","award":["NRF2021R1C1C1013220"],"award-info":[{"award-number":["NRF2021R1C1C1013220"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"MSIT","doi-asserted-by":"publisher","award":["RS-2022-NR070833"],"award-info":[{"award-number":["RS-2022-NR070833"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"MSIT","doi-asserted-by":"publisher","award":["RS-2023-00223069"],"award-info":[{"award-number":["RS-2023-00223069"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"MSIT","doi-asserted-by":"publisher","award":["RS-2023-00211612"],"award-info":[{"award-number":["RS-2023-00211612"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"MSIT","doi-asserted-by":"publisher","award":["RS-2024-00411768"],"award-info":[{"award-number":["RS-2024-00411768"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"MSIT","doi-asserted-by":"publisher","award":["RS-2025024523684"],"award-info":[{"award-number":["RS-2025024523684"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014188","name":"MSIT","doi-asserted-by":"publisher","award":["RS-2025-02217909"],"award-info":[{"award-number":["RS-2025-02217909"]}],"id":[{"id":"10.13039\/501100014188","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004332","name":"Seoul National University Hospital","doi-asserted-by":"publisher","award":["550-20250081"],"award-info":[{"award-number":["550-20250081"]}],"id":[{"id":"10.13039\/501100004332","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Republic of Korea","award":["22B-001-0100"],"award-info":[{"award-number":["22B-001-0100"]}]},{"DOI":"10.13039\/501100002551","name":"Seoul National University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002551","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017051","name":"Seoul National University College of Medicine","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100017051","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004917","name":"Doosan Yonkang Foundation","doi-asserted-by":"publisher","award":["SNUH-30-2024-0440"],"award-info":[{"award-number":["SNUH-30-2024-0440"]}],"id":[{"id":"10.13039\/501100004917","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100022745","name":"NAVER","doi-asserted-by":"publisher","award":["SNUH-3720242170"],"award-info":[{"award-number":["SNUH-3720242170"]}],"id":[{"id":"10.13039\/100022745","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Korean government"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Polycomb repressive complex 2 (PRC2) represses genes through catalyzing H3K27me3, a histone modification essential for maintenance of cellular identity. The complex\u2019s catalytic activity, chromatin localization, and propagation along chromatin are modulated by accessory proteins such as AEBP2, MTF2, JARID2, and PALI, which is specifically required for mouse embryogenesis. AEBP2 exists in distinct isoforms: a short isoform that enhances PRC2 catalytic activity and promotes H3K27me3 spreading, facilitating robust gene repression, and a long isoform whose function has remained unclear. Here, we report that the N-terminal region of the long isoform contains conserved DE-motifs unique to this isoform that inhibit PRC2 activity, including both H3K27 methylation and EZH2 automethylation, suggesting that these motifs interfere with the automethylation loop proximal to the SET domain. Notably, re-expression of the long isoform in Mtf2\/Jarid2\/Aebp2 triple-knockout mouse embryonic stem cells failed to restore H3K27me3 and caused defective differentiation. These findings uncover an isoform-specific regulatory mechanism by which AEBP2 controls PRC2 activity and contributes to a broader understanding of the dynamic regulation of PRC2 during development.<\/jats:p>","DOI":"10.1093\/nar\/gkag694","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T11:14:09Z","timestamp":1783595649000},"source":"Crossref","is-referenced-by-count":0,"title":["Opposing function of AEBP2 isoforms fine-tune PRC2 catalytic activity"],"prefix":"10.1093","volume":"54","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3938-4761","authenticated-orcid":false,"given":"Yingying","family":"Li","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Seoul National University College of Medicine , Seoul, 03080 ,","place":["Republic of Korea"]},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine , Seoul, 03080,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3699-8245","authenticated-orcid":false,"given":"Cheolan","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Seoul National University College of Medicine , Seoul, 03080 ,","place":["Republic of Korea"]},{"name":"Cancer Research Institute, Ischemic\/hypoxic Disease Institute, Neuroscience Research Institute, The Institute of Molecular Biology & Genetics, Seoul National University, Seoul National University , Seoul, 03080 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanbyeol","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Seoul National University College of Medicine , Seoul, 03080 ,","place":["Republic of Korea"]},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine , Seoul, 03080,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0643-0100","authenticated-orcid":false,"given":"Chul-Hwan","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Seoul National University College of Medicine , Seoul, 03080 ,","place":["Republic of Korea"]},{"name":"Department of Biomedical Sciences, Seoul National University College of Medicine , Seoul, 03080,","place":["Republic of Korea"]},{"name":"Cancer Research Institute, Ischemic\/hypoxic Disease Institute, Neuroscience Research Institute, The Institute of Molecular Biology & Genetics, Seoul National University, Seoul National University , Seoul, 03080 ,","place":["Republic of Korea"]},{"name":"Wide River Institute of Immunology, Seoul National University , Hongcheon, 25159 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"2026081001112193900_B1","doi-asserted-by":"publisher","first-page":"595","DOI":"10.5483\/BMBRep.2022.55.12.174","article-title":"The role of EZH1 and EZH2 in development and cancer","volume":"55","author":"Lee","year":"2022","journal-title":"BMB Rep"},{"key":"2026081001112193900_B2","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1101\/gad.325050.119","article-title":"PRC2 is high maintenance","volume":"33","author":"Yu","year":"2019","journal-title":"Genes Dev"},{"key":"2026081001112193900_B3","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1101\/gad.381706","article-title":"Genome-wide mapping of Polycomb target genes unravels their roles in cell fate transitions","volume":"20","author":"Bracken","year":"2006","journal-title":"Genes Dev"},{"key":"2026081001112193900_B4","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/j.cell.2007.05.009","article-title":"High-resolution profiling of histone methylations in the human genome","volume":"129","author":"Barski","year":"2007","journal-title":"Cell"},{"key":"2026081001112193900_B5","doi-asserted-by":"publisher","first-page":"422","DOI":"10.1016\/j.molcel.2018.03.020","article-title":"Allosteric activation dictates PRC2 activity independent of its recruitment to chromatin","volume":"70","author":"Lee","year":"2018","journal-title":"Mol Cell"},{"key":"2026081001112193900_B6","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1038\/nature08398","article-title":"Role of the polycomb protein EED in the propagation of repressive histone marks","volume":"461","author":"Margueron","year":"2009","journal-title":"Nature"},{"key":"2026081001112193900_B7","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.molcel.2018.03.019","article-title":"Distinct stimulatory mechanisms regulate the catalytic activity of polycomb repressive complex 2","volume":"70","author":"Lee","year":"2018","journal-title":"Mol Cell"},{"key":"2026081001112193900_B8","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1038\/nature23881","article-title":"Polycomb-like proteins link the PRC2 complex to CpG islands","volume":"549","author":"Li","year":"2017","journal-title":"Nature"},{"key":"2026081001112193900_B9","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.1016\/j.molcel.2018.05.023","article-title":"Capturing the onset of PRC2-mediated repressive domain formation","volume":"70","author":"Oksuz","year":"2018","journal-title":"Mol Cell"},{"key":"2026081001112193900_B10","doi-asserted-by":"publisher","first-page":"840","DOI":"10.1016\/j.molcel.2018.01.039","article-title":"Unique structural platforms of Suz12 dictate distinct classes of PRC2 for chromatin binding","volume":"69","author":"Chen","year":"2018","journal-title":"Mol Cell"},{"key":"2026081001112193900_B11","doi-asserted-by":"publisher","first-page":"2663","DOI":"10.1101\/gad.225888.113","article-title":"Nucleosome-binding activities within JARID2 and EZH1 regulate the function of PRC2 on chromatin","volume":"27","author":"Son","year":"2013","journal-title":"Genes Dev"},{"key":"2026081001112193900_B12","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1038\/nsmb.2449","article-title":"Polycomb PHF19 binds H3K36me3 and recruits PRC2 and demethylase NO66 to embryonic stem cell genes during differentiation","volume":"19","author":"Brien","year":"2012","journal-title":"Nat Struct Mol Biol"},{"key":"2026081001112193900_B13","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1080\/15592294.2015.1042646","article-title":"An aromatic cage is required but not sufficient for binding of Tudor domains of the Polycomblike protein family to H3K36me3","volume":"10","author":"Gatchalian","year":"2015","journal-title":"Epigenetics"},{"key":"2026081001112193900_B14","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1002\/stem.578","article-title":"PRC2 complexes with JARID2, MTF2, and esPRC2p48 in ES cells to modulate ES cell pluripotency and somatic cell reprograming","volume":"29","author":"Zhang","year":"2011","journal-title":"Stem Cells"},{"key":"2026081001112193900_B15","doi-asserted-by":"publisher","first-page":"940","DOI":"10.1126\/science.aar5700","article-title":"Structures of human PRC2 with its cofactors AEBP2 and JARID2","volume":"359","author":"Kasinath","year":"2018","journal-title":"Science"},{"key":"2026081001112193900_B16","doi-asserted-by":"publisher","first-page":"2625","DOI":"10.1016\/j.molcel.2021.03.038","article-title":"Distinct PRC2 subunits regulate maintenance and establishment of Polycomb repression during differentiation","volume":"81","author":"Petracovici","year":"2021","journal-title":"Mol Cell"},{"key":"2026081001112193900_B17","doi-asserted-by":"publisher","first-page":"e25174","DOI":"10.1371\/journal.pone.0025174","article-title":"Aebp2 as an epigenetic regulator for neural crest cells","volume":"6","author":"Kim","year":"2011","journal-title":"PLoS One"},{"key":"2026081001112193900_B18","doi-asserted-by":"publisher","first-page":"2716","DOI":"10.1242\/dev.123935","article-title":"Functional analysis of AEBP2, a PRC2 Polycomb protein, reveals a Trithorax phenotype in embryonic development and in ESCs","volume":"143","author":"Grijzenhout","year":"2016","journal-title":"Development"},{"key":"2026081001112193900_B19","doi-asserted-by":"crossref","first-page":"eabc3393","DOI":"10.1126\/science.abc3393","article-title":"JARID2 and AEBP2 regulate PRC2 in the presence of H2AK119ub1 and other histone modifications","volume":"371","author":"Kasinath","year":"2021","journal-title":"Science"},{"key":"2026081001112193900_B20","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.ygeno.2014.11.007","article-title":"AEBP2 as a transcriptional activator and its role in cell migration","volume":"105","author":"Kim","year":"2015","journal-title":"Genomics"},{"key":"2026081001112193900_B21","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1006\/jmbi.1997.1235","article-title":"Characterization of nucleosome core particles containing histone proteins made in bacteria","volume":"272","author":"Luger","year":"1997","journal-title":"J Mol Biol"},{"key":"2026081001112193900_B22","first-page":"109","article-title":"Techniques to Study Automethylation of Histone Methyltransferases and its Functional Impact","volume-title":"Methods Mol Biol","author":"Popoca","year":"2022"},{"key":"2026081001112193900_B23","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1101\/gad.328773.119","article-title":"Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma","volume":"33","author":"Lee","year":"2019","journal-title":"Genes Dev"},{"key":"2026081001112193900_B24","doi-asserted-by":"publisher","first-page":"1416","DOI":"10.1101\/gad.328849.119","article-title":"Regulation of histone methylation by automethylation of PRC2","volume":"33","author":"Wang","year":"2019","journal-title":"Genes Dev"},{"key":"2026081001112193900_B25","doi-asserted-by":"publisher","first-page":"6979","DOI":"10.1038\/s44318-025-00616-9","article-title":"Auto-inhibition of PRC2 by the broadly expressed long isoform of AEBP2","volume":"44","author":"Mucha","year":"2025","journal-title":"EMBO J"},{"key":"2026081001112193900_B26","doi-asserted-by":"publisher","first-page":"35","DOI":"10.12688\/f1000research.2-35.v1","article-title":"Longitudinal RNA sequencing of the deep transcriptome during neurogenesis of cortical glutamatergic neurons from murine ESCs","volume":"2","author":"Hubbard","year":"2013","journal-title":"F1000Res"},{"key":"2026081001112193900_B27","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.molcel.2019.07.031","article-title":"Non-core subunits of the PRC2 complex are collectively required for its target-site specificity","volume":"76","author":"H\u00f8jfeldt","year":"2019","journal-title":"Mol Cell"},{"key":"2026081001112193900_B28","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1016\/j.molcel.2019.08.012","article-title":"PRC2.1 and PRC2.2 synergize to coordinate H3K27 trimethylation","volume":"76","author":"Healy","year":"2019","journal-title":"Mol Cell"},{"key":"2026081001112193900_B29","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.molcel.2019.03.011","article-title":"Molecular mechanisms directing PRC2 recruitment and H3K27 methylation","volume":"74","author":"Laugesen","year":"2019","journal-title":"Mol Cell"},{"key":"2026081001112193900_B30","doi-asserted-by":"publisher","first-page":"e2527303123","DOI":"10.1073\/pnas.2527303123","article-title":"EPOP and MTF2 activate PRC2 activity through DNA-sequence specificity","volume":"123","author":"Granat","year":"2026","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026081001112193900_B31","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s13072-020-00369-1","article-title":"Post-translational modifications of PRC2: signals directing its activity","volume":"13","author":"Yang","year":"2020","journal-title":"Epigenetics Chromatin"},{"key":"2026081001112193900_B32","doi-asserted-by":"publisher","first-page":"eaax2887","DOI":"10.1126\/sciadv.aax2887","article-title":"CATACOMB: an endogenous inducible gene that antagonizes H3K27 methylation activity of Polycomb repressive complex 2 via an H3K27M-like mechanism","volume":"5","author":"Piunti","year":"2019","journal-title":"Sci Adv"},{"key":"2026081001112193900_B33","doi-asserted-by":"publisher","first-page":"2146","DOI":"10.1038\/s41467-019-09981-6","article-title":"PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism","volume":"10","author":"Jain","year":"2019","journal-title":"Nat Commun"},{"key":"2026081001112193900_B34","doi-asserted-by":"publisher","first-page":"4876","DOI":"10.1016\/j.molcel.2021.10.008","article-title":"Histone H3.3 K27M and K36M mutations de-repress transposable elements through perturbation of antagonistic chromatin marks","volume":"81","author":"Chaouch","year":"2021","journal-title":"Mol Cell"},{"key":"2026081001112193900_B35","doi-asserted-by":"publisher","first-page":"eaau5935","DOI":"10.1126\/sciadv.aau5935","article-title":"Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma","volume":"4","author":"Stafford","year":"2018","journal-title":"Sci Adv"},{"key":"2026081001112193900_B36","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/s41594-024-01452-x","article-title":"Structural basis for the inhibition of PRC2 by active transcription histone posttranslational modifications","volume":"32","author":"Cookis","year":"2025","journal-title":"Nat Struct Mol Biol"},{"key":"2026081001112193900_B37","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1038\/s41588-024-01740-8","article-title":"Inseparable RNA binding and chromatin modification activities of a nucleosome-interacting surface in EZH2","volume":"56","author":"Gail","year":"2024","journal-title":"Nat Genet"},{"key":"2026081001112193900_B38","doi-asserted-by":"publisher","first-page":"e31558","DOI":"10.7554\/eLife.31558","article-title":"Conserved RNA-binding specificity of polycomb repressive complex 2 is achieved by dispersed amino acid patches in EZH2","volume":"6","author":"Long","year":"2017","journal-title":"eLife"},{"key":"2026081001112193900_B39","doi-asserted-by":"publisher","first-page":"643","DOI":"10.1016\/j.ccell.2018.08.018","article-title":"HOXA9 reprograms the enhancer landscape to promote leukemogenesis","volume":"34","author":"Sun","year":"2018","journal-title":"Cancer Cell"},{"key":"2026081001112193900_B40","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1038\/s41556-022-00932-w","article-title":"Integrated multi-omics reveal polycomb repressive complex 2 restricts human trophoblast induction","volume":"24","author":"Zijlmans","year":"2022","journal-title":"Nat Cell Biol"},{"key":"2026081001112193900_B41","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1126\/science.1232245","article-title":"Inhibition of PRC2 activity by a gain-of-function H3 mutation found in pediatric glioblastoma","volume":"340","author":"Lewis","year":"2013","journal-title":"Science"},{"key":"2026081001112193900_B42","doi-asserted-by":"publisher","first-page":"3454","DOI":"10.1242\/jcs.102061","article-title":"Polycomb repressive complex 2 impedes intestinal cell terminal differentiation","volume":"125","author":"Benoit","year":"2012","journal-title":"J Cell Sci"},{"key":"2026081001112193900_B43","doi-asserted-by":"crossref","first-page":"eabb2745","DOI":"10.1126\/sciadv.abb2745","article-title":"The Polycomb-associated factor PHF19 controls hematopoietic stem cell state and differentiation","volume":"6","author":"Viz\u00e1n","year":"2020","journal-title":"Sci Adv"},{"key":"2026081001112193900_B44","first-page":"650","article-title":"The conserved N-terminal SANT1-binding domain (SBD) of EZH2 regulates PRC2 activity","volume-title":"Genes Dev","author":"Patriotis","year":"2026"},{"key":"2026081001112193900_B45","doi-asserted-by":"publisher","first-page":"1049","DOI":"10.1016\/j.molcel.2024.02.011","article-title":"Alternative splicing decouples local from global PRC2 activity","volume":"84","author":"Arecco","year":"2024","journal-title":"Mol Cell"},{"key":"2026081001112193900_B46","doi-asserted-by":"publisher","first-page":"666","DOI":"10.1101\/gad.353014.125","article-title":"Chromatin binding and N-terminal domains of DNMT3B1 confer specificity for developmentally regulated CpG island methylation","volume":"40","author":"Yasmin","year":"2026","journal-title":"Genes Dev"}],"container-title":["Nucleic Acids Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/13\/gkag694\/68738420\/gkag694.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/nar\/article-pdf\/54\/13\/gkag694\/68738420\/gkag694.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T05:13:49Z","timestamp":1786338829000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/nar\/article\/doi\/10.1093\/nar\/gkag694\/8729023"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,3]]},"references-count":46,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2026,7,3]]}},"URL":"https:\/\/doi.org\/10.1093\/nar\/gkag694","relation":{},"ISSN":["0305-1048","1362-4962"],"issn-type":[{"value":"0305-1048","type":"print"},{"value":"1362-4962","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,7,22]]},"published":{"date-parts":[[2026,7,3]]},"article-number":"gkag694"}}