{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T18:07:30Z","timestamp":1791223650312,"version":"4.1.0"},"reference-count":90,"publisher":"American Chemical Society (ACS)","issue":"30","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100004921","name":"Shanghai Jiao Tong University","doi-asserted-by":"publisher","award":["WH510363004\/013"],"award-info":[{"award-number":["WH510363004\/013"]}],"id":[{"id":"10.13039\/501100004921","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanghai Key Laboratory for Antibody-Drug Conjugates with Innovative Target, Shanghai Jiao Tong University","award":["24dz2261300"],"award-info":[{"award-number":["24dz2261300"]}]},{"name":"Natural Science Foundation of Shanghai","award":["25ZR1402193"],"award-info":[{"award-number":["25ZR1402193"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China (NSFC)","doi-asserted-by":"crossref","award":["22177085"],"award-info":[{"award-number":["22177085"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China (NSFC)","doi-asserted-by":"crossref","award":["22477092"],"award-info":[{"award-number":["22477092"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China (NSFC)","doi-asserted-by":"crossref","award":["32501108"],"award-info":[{"award-number":["32501108"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Shanghai Frontiers Science Center of Drug Target Identification and Delivery, Shanghai Jiao Tong University","award":["ZXWH2170101"],"award-info":[{"award-number":["ZXWH2170101"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The activation of UHRF1 E3 ligase by the H3K9me3 mark is critical for epigenetic inheritance; however, its precise mode of action within asymmetric nucleosomes remains unclear. Here, we leveraged the SpyTag\/SpyCatcher bioorthogonal system to synthesize nucleosomes with predefined chemical asymmetry\u2500an approach that enables clear spatial discrimination between the H3K9me3 recognition site and ubiquitin-acceptor lysines. Employing these synthetic, structurally defined nucleosomes, we found that H3K9me3 preferentially activates UHRF1 via an intramolecular (in cis) mechanism. Subsequent biochemical analyses demonstrated that this process depends on the physical coupling of two key UHRF1 functions: its synergistic recognition of the H3K9me3 modification and UHRF1\u2019s catalytic activity on the same H3 tail. In contrast, an H3K9me3 mark present on the opposing H3 monomer fails to significantly stimulate ubiquitination. To elucidate the structural basis of this cis activation, we further chemically synthesized a stable mimetic of the cis-activated UHRF1\/UbcH5b\u2013Ub\/H3K9me3 nucleosome complex using CAET-mediated conjugation and split-intein splicing chemistry. Cross-linking mass spectrometry (XL-MS) analyses of this complex mapped the interaction networks among domains within UHRF1, between UHRF1 and histones, and between the E2\u2013Ub module and the nucleosome core. These data yield spatial insights into UHRF1 activity on the nucleosome. Our study provides the first direct evidence for cis-activation of UHRF1 by H3K9me3 at the nucleosomal level, while highlighting the utility of chemical biology for deciphering complex epigenetic processes.<\/jats:p>","DOI":"10.1021\/jacs.6c10014","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T16:45:27Z","timestamp":1784738727000},"page":"32630-32643","source":"Crossref","is-referenced-by-count":1,"title":["Chemical Synthesis\nof Asymmetric Nucleosomes Reveals\nIntramolecular Activation of UHRF1 E3 Ligase by H3K9me3"],"prefix":"10.1021","volume":"148","author":[{"given":"Ziyu","family":"Xu","sequence":"first","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]},{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zebin","family":"Tong","sequence":"additional","affiliation":[{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-8459-0262","authenticated-orcid":true,"given":"Tianyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Tsinghua University , , ,","place":["Beijing, China, 100084"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Liu","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5308-5787","authenticated-orcid":true,"given":"Jia-Bin","family":"Li","sequence":"additional","affiliation":[{"name":"Soochow University , , ,","place":["Suzhou, China, 215123"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3378-5874","authenticated-orcid":true,"given":"Huasong","family":"Ai","sequence":"additional","affiliation":[{"name":"Shanghai Jiao Tong University , , ,","place":["Shanghai, China, 200240"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"issue":"10","key":"2026080511110655500_cit1","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/s41580-019-0159-6","article-title":"The diverse roles of DNA methylation\nin mammalian development and disease","volume":"20","author":"Greenberg","year":"2019","journal-title":"Nat. Rev.\nMol. Cell Biol."},{"issue":"1","key":"2026080511110655500_cit2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1038\/s41576-024-00760-8","article-title":"DNA methylation in\nmammalian development\nand disease","volume":"26","author":"Smith","year":"2025","journal-title":"Nat. Rev. Genet."},{"key":"2026080511110655500_cit3","doi-asserted-by":"publisher","DOI":"10.1266\/ggs.25-00051","article-title":"A comprehensive review of structural\ninsights into DNA methylation maintenance","volume":"100","author":"Kikuchi","year":"2025","journal-title":"Genes Genet. Syst."},{"issue":"6","key":"2026080511110655500_cit4","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.1093\/nar\/gkp1152","article-title":"The multi-domain protein Np95 connects\nDNA methylation\nand histone modification","volume":"38","author":"Rottach","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"2026080511110655500_cit5","doi-asserted-by":"publisher","first-page":"1563","DOI":"10.1038\/ncomms2562","article-title":"UHRF1 targets DNMT1 for DNA methylation\nthrough cooperative binding of hemi-methylated DNA and methylated\nH3K9","volume":"4","author":"Liu","year":"2013","journal-title":"Nat. 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Biol. Chem."},{"issue":"32","key":"2026080511110655500_cit12","doi-asserted-by":"publisher","first-page":"12950","DOI":"10.1073\/pnas.1203701109","article-title":"Recognition of modification status on a histone H3\ntail by linked histone reader modules of the epigenetic regulator\nUHRF1","volume":"109","author":"Arita","year":"2012","journal-title":"P. Natl. Acad. Sci. USA"},{"issue":"2","key":"2026080511110655500_cit13","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.jmb.2011.11.012","article-title":"UHRF1 Double\nTudor Domain and the\nAdjacent PHD Finger Act Together to Recognize K9me3-Containing Histone\nH3 Tail","volume":"415","author":"Xie","year":"2012","journal-title":"J. Mol. 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Allerg Immu"},{"key":"2026080511110655500_cit24","doi-asserted-by":"publisher","DOI":"10.7554\/elife.62682","article-title":"SUV39 SET domains mediate\ncrosstalk of heterochromatic histone marks","volume":"10","author":"Stirpe","year":"2021","journal-title":"eLife"},{"issue":"8","key":"2026080511110655500_cit25","doi-asserted-by":"publisher","first-page":"1442","DOI":"10.1021\/acscentsci.4c00642","article-title":"Chemical Synthesis\nof Human Proteoforms and Application\nin Biomedicine","volume":"10","author":"Ai","year":"2024","journal-title":"ACS Cent. Sci."},{"key":"2026080511110655500_cit26","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1007\/s11426-024-1950-1","article-title":"Recent advances in chemical\nprotein synthesis: method developments and biological applications","volume":"67","author":"Dong","year":"2024","journal-title":"Sci. China Chem."},{"issue":"9","key":"2026080511110655500_cit27","doi-asserted-by":"publisher","first-page":"2515","DOI":"10.1007\/s11427-024-2860-5","article-title":"Advances in the chemical\nsynthesis of human proteoforms","volume":"68","author":"Yang","year":"2025","journal-title":"Sci. China Life\nSci."},{"issue":"1","key":"2026080511110655500_cit28","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202413651","article-title":"Promotion of RNF168-Mediated\nNucleosomal H2A Ubiquitylation by Structurally Defined K63-Polyubiquitylated\nLinker Histone H1","volume":"64","author":"Shi","year":"2025","journal-title":"Angew. Chem., Int. Ed."},{"issue":"40","key":"2026080511110655500_cit29","doi-asserted-by":"publisher","first-page":"18329","DOI":"10.1021\/jacs.2c06156","article-title":"Chemical Synthesis of\nPost-Translationally Modified H2AX Reveals\nRedundancy in Interplay between Histone Phosphorylation, Ubiquitination,\nand Methylation on the Binding of 53BP1 with Nucleosomes","volume":"144","author":"Ai","year":"2022","journal-title":"J. Am. Chem. Soc."},{"issue":"8","key":"2026080511110655500_cit30","doi-asserted-by":"publisher","first-page":"3360","DOI":"10.1021\/jacs.1c13555","article-title":"Histone H2B Deacylation Selectivity: Exploring Chromatin\u2019s\nDark Matter with an Engineered Sortase","volume":"144","author":"Wang","year":"2022","journal-title":"J. Am.\nChem. 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Soc."},{"issue":"15","key":"2026080511110655500_cit45","doi-asserted-by":"publisher","first-page":"3704","DOI":"10.1039\/C8SC00681D","article-title":"A bi-terminal\nprotein\nligation strategy to probe chromatin structure during DNA damage","volume":"9","author":"Kilic","year":"2018","journal-title":"Chem. 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Sci."},{"issue":"84","key":"2026080511110655500_cit48","doi-asserted-by":"publisher","first-page":"12639","DOI":"10.1039\/C9CC05526F","article-title":"Thiirane\nlinkers directed histone\nH2A diubiquitination suggests plasticity in 53BP1 recognition","volume":"55","author":"Liang","year":"2019","journal-title":"Chem. Commun."},{"issue":"46","key":"2026080511110655500_cit49","doi-asserted-by":"publisher","first-page":"42647","DOI":"10.1021\/jacs.5c13964","article-title":"Chemical Engineering of Transcription Factors\nUncovered Cell-Permeable \u03bcMax Modulators","volume":"147","author":"Harel","year":"2025","journal-title":"J. Am. Chem. Soc."},{"issue":"37","key":"2026080511110655500_cit50","doi-asserted-by":"publisher","first-page":"25788","DOI":"10.1021\/jacs.4c08416","article-title":"A Versatile Method for Site-Specific\nChemical Installation of Aromatic Posttranslational Modification Analogs\ninto Proteins","volume":"146","author":"Lin","year":"2024","journal-title":"J. Am. Chem. 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