title: Histone methyltransferase MLL3 contributes to genome-scale circadian transcription.
abstract: Daily cyclical expression of thousands of genes in tissues such as the liver is orchestrated by the molecular circadian clock, the disruption of which is implicated in metabolic disorders and cancer. Although we understand much about the circadian transcription factors that can switch gene expression on and off, it is still unclear how global changes in rhythmic transcription are controlled at the genomic level. Here, we demonstrate circadian modification of an activating histone mark at a significant proportion of gene loci that undergo daily transcription, implicating widespread epigenetic modification as a key node regulated by the clockwork. Furthermore, we identify the histone-remodelling enzyme mixed lineage leukemia (MLL)3 as a clock-controlled factor that is able to directly and indirectly modulate over a hundred epigenetically targeted circadian "output" genes in the liver. Importantly, catalytic inactivation of the histone methyltransferase activity of MLL3 also severely compromises the oscillation of "core" clock gene promoters, including Bmal1, mCry1, mPer2, and Rev-erbα, suggesting that rhythmic histone methylation is vital for robust transcriptional oscillator function. This highlights a pathway by which the clockwork exerts genome-wide control over transcription, which is critical for sustaining temporal programming of tissue physiology.
authors.affiliation: Department of Clinical Neurosciences, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital,  University of Cambridge, Cambridge CB2 0QQ,  United Kingdom.
authors.forename: Utham K
authors.initials: UK
authors.lastname: Valekunja
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Edgar
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Oklejewicz
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
authors.forename: John S
authors.initials: JS
authors.lastname: O'Neill
authors.forename: Filippo
authors.initials: F
authors.lastname: Tamanini
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Turner
authors.forename: Akhilesh B
authors.initials: AB
authors.lastname: Reddy
mesh_terms: D056930:ARNTL Transcription Factors / Q000235:genetics; D000818:Animals; D002460:Cell Line; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology*; D056931:Cryptochromes / Q000172:deficiency / Q000235:genetics; D057890:Epigenomics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000235:genetics; D056950:Period Circadian Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D049490:Systems Biology; D014158:Transcription, Genetic; D004268:DNA-Binding Proteins
chemical_list: D056930:ARNTL Transcription Factors; D056931:Cryptochromes; D011495:Histone-Lysine N-Methyltransferase; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D056950:Period Circadian Proteins; C538961:Bmal1 protein, mouse; C538964:Cry1 protein, mouse; C538967:Cry2 protein, mouse; C498262:Nr1d1 protein, mouse; C513312:Per2 protein, mouse; C510652:Kmt2c protein, mouse; D004268:DNA-Binding Proteins