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Dysregulation of H4K20me3 and KMT5C, the major methyltransferase for H4K20me3, occurs commonly in multiple types of cancer but the mechanisms surrounding how they contribute to shaping the epigenomic landscape remains unclear. Here, we show that KMT5C is involved in non-canonical deposition of H4K20me3, independent of H3K9me3, which was previously recognized as a prerequisite for H4K20me3. This novel subtype of H4K20me3 lacks canonical repressive epigenetic signatures and instead overlaps with multiple activating marks. These activating modifications likely contribute to the dynamic changes in transcript levels upon loss of H4K20me3. The mechanism involved in recruiting KMT5C to these loci is independent of HP1, the factor reported to be involved in recruitment of KMT5C to heterochromatin marked with H3K9me3. Instead, biochemical analyses revealed ZNF280C to be a novel interacting partner of KMT5C, with ZNF280C localizing specifically at H3K9me3-\/H4K20me3+ sites. Together, these results suggest a novel, non-canonical function of KMT5C-H4K20me3 that protects vulnerable regions of the genome from uncontrolled expression.<\/jats:p>","DOI":"10.64898\/2026.05.11.724304","type":"posted-content","created":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:10:27Z","timestamp":1778778627000},"source":"Crossref","is-referenced-by-count":0,"title":["KMT5C-H4K20me3 drives changes in epigenetic landscape independent of H3K9me3"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0316-1833","authenticated-orcid":false,"given":"Jihye","family":"Son","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6652-1197","authenticated-orcid":false,"given":"Ching-Hua","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Biomedical Genetics and the Wilmot Cancer Institute, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Davidson","sequence":"additional","affiliation":[{"name":"Department of Biomedical Genetics and the Wilmot Cancer Institute, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3453-1948","authenticated-orcid":false,"given":"Sagar M.","family":"Utturkar","sequence":"additional","affiliation":[{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2675-652X","authenticated-orcid":false,"given":"Nathaniel W.","family":"Mabe","sequence":"additional","affiliation":[{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexandra","family":"Glaws","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6165-2019","authenticated-orcid":false,"given":"Paula M.","family":"Vertino","sequence":"additional","affiliation":[{"name":"Department of Biomedical Genetics and the Wilmot Cancer Institute, University of Rochester, Rochester, NY 14642, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9602-7827","authenticated-orcid":false,"given":"Andrea L.","family":"Kasinski","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN 47907, USA"},{"name":"Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026051621100541000_2026.05.11.724304v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/47412"},{"key":"2026051621100541000_2026.05.11.724304v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-021-00357-x"},{"key":"2026051621100541000_2026.05.11.724304v1.3","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"2026051621100541000_2026.05.11.724304v1.4","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-24-0296"},{"key":"2026051621100541000_2026.05.11.724304v1.5","first-page":"OF1","article-title":"Loss of KMT5C Promotes EGFR Inhibitor Resistance in NSCLC via LINC01510-Mediated Upregulation of MET","volume":"82","year":"2022","journal-title":"Cancer Res"},{"key":"2026051621100541000_2026.05.11.724304v1.6","doi-asserted-by":"crossref","unstructured":"Broeck AVD , Brambilla E , Moro-Sibilot D , Lantuejoul S , Brambilla C , Eymin B , et al. 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