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The core cellular circadian clock is a transcription\u2013translation negative feedback loop, which can recruit epigenetic regulators to facilitate temporal control of gene expression. Histone methyltransferase, mixed lineage leukemia gene 3 (MLL3) was reported to be required for the maintenance of circadian oscillations in cultured cells. Here, we test the role of MLL3 in circadian organization in whole animals. Using mice expressing catalytically inactive MLL3, we show that MLL3\u00a0methyltransferase activity is in fact not required for circadian oscillations\u00a0in vitro\u00a0in a range of tissues, nor for the maintenance of circadian behavioral rhythms\u00a0in vivo. In contrast to a previous report, loss of MLL3\u2010dependent methylation did not affect the global levels of H3K4\u00a0methylation in liver, indicating substantial compensation from other methyltransferases. Furthermore, we found little evidence of genomic repositioning of H3K4me3\u00a0marks. We did, however, observe repositioning of H3K4me1 from intronic regions to intergenic regions and gene promoters; however, there were no changes in H3K4me1\u00a0mark abundance around core circadian clock genes. Output functions of the circadian clock, such as control of inflammation, were largely intact in MLL3\u2010methyltransferase\u2010deficient mice, although some gene\u2010specific changes were observed, with sexually dimorphic loss of circadian regulation of specific cytokines. Taken together, these observations indicate that MLL3\u2010directed histone methylation is not essential for core circadian clock function; however, it may influence the inflammatory response.<\/jats:p>","DOI":"10.1096\/fj.202200368r","type":"journal-article","created":{"date-parts":[[2022,6,15]],"date-time":"2022-06-15T10:54:46Z","timestamp":1655290486000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Circadian clock function does not require the histone methyltransferase MLL3"],"prefix":"10.1096","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3612-2574","authenticated-orcid":false,"given":"Matthew","family":"Baxter","sequence":"first","affiliation":[{"name":"NIHR Oxford Biomedical Research Centre John Radcliffe Hospital  Oxford UK"},{"name":"Oxford Centre for Diabetes, Endocrinology and Metabolism University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toryn","family":"Poolman","sequence":"additional","affiliation":[{"name":"NIHR Oxford Biomedical Research Centre John Radcliffe Hospital  Oxford UK"},{"name":"Oxford Centre for Diabetes, Endocrinology and Metabolism University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Centre for Biological Timing Faculty of Biology, Medicine and Health University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Hunter","sequence":"additional","affiliation":[{"name":"Centre for Biological Timing Faculty of Biology, Medicine and Health University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Voronkov","sequence":"additional","affiliation":[{"name":"NIHR Oxford Biomedical Research Centre John Radcliffe Hospital  Oxford UK"},{"name":"Oxford Centre for Diabetes, Endocrinology and Metabolism University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5070-3183","authenticated-orcid":false,"given":"Gareth B.","family":"Kitchen","sequence":"additional","affiliation":[{"name":"Centre for Biological Timing Faculty of Biology, Medicine and Health University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Goosey","sequence":"additional","affiliation":[{"name":"Centre for Biological Timing Faculty of Biology, Medicine and Health University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Begley","sequence":"additional","affiliation":[{"name":"Centre for Biological Timing Faculty of Biology, Medicine and Health University of Manchester  Manchester UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Kay","sequence":"additional","affiliation":[{"name":"NIHR Oxford Biomedical Research Centre John Radcliffe Hospital  Oxford UK"},{"name":"Oxford Centre for Diabetes, Endocrinology and Metabolism University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abby","family":"Hespe","sequence":"additional","affiliation":[{"name":"NIHR Oxford Biomedical Research Centre John Radcliffe Hospital  Oxford UK"},{"name":"Oxford Centre for Diabetes, Endocrinology and Metabolism University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Maidstone","sequence":"additional","affiliation":[{"name":"NIHR Oxford Biomedical Research Centre John Radcliffe Hospital  Oxford UK"},{"name":"Oxford Centre for Diabetes, Endocrinology and Metabolism University of Oxford  Oxford UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3648-445X","authenticated-orcid":false,"given":"Andrew S. 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