title: Mll2 is required for H3K4 trimethylation on bivalent promoters in embryonic stem cells, whereas Mll1 is redundant.
abstract: Trimethylation of histone H3 lysine 4 (H3K4me3) at the promoters of actively transcribed genes is a universal epigenetic mark and a key product of Trithorax group action. Here, we show that Mll2, one of the six Set1/Trithorax-type H3K4 methyltransferases in mammals, is required for trimethylation of bivalent promoters in mouse embryonic stem cells. Mll2 is bound to bivalent promoters but also to most active promoters, which do not require Mll2 for H3K4me3 or mRNA expression. By contrast, the Set1 complex (Set1C) subunit Cxxc1 is primarily bound to active but not bivalent promoters. This indicates that bivalent promoters rely on Mll2 for H3K4me3 whereas active promoters have more than one bound H3K4 methyltransferase, including Set1C. Removal of Mll1, sister to Mll2, had almost no effect on any promoter unless Mll2 was also removed, indicating functional backup between these enzymes. Except for a subset, loss of H3K4me3 on bivalent promoters did not prevent responsiveness to retinoic acid, thereby arguing against a priming model for bivalency. In contrast, we propose that Mll2 is the pioneer trimethyltransferase for promoter definition in the naïve epigenome and that Polycomb group action on bivalent promoters blocks the premature establishment of active, Set1C-bound, promoters.
authors.affiliation: Department of Molecular Biology, Faculty of Science, Nijmegen Centre for Molecular Life Sciences (NCMLS), Radboud University, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
authors.forename: Sergei
authors.initials: S
authors.lastname: Denissov
authors.forename: Helmut
authors.initials: H
authors.lastname: Hofemeister
authors.forename: Hendrik
authors.initials: H
authors.lastname: Marks
authors.forename: Andrea
authors.initials: A
authors.lastname: Kranz
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ciotta
authors.forename: Sukhdeep
authors.initials: S
authors.lastname: Singh
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Anastassiadis
authors.forename: Hendrik G
authors.initials: HG
authors.lastname: Stunnenberg
authors.forename: A Francis
authors.initials: AF
authors.lastname: Stewart
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D022202:Chromosomes, Artificial, Bacterial / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D016678:Genome / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism*; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008954:Models, Biological; D051788:Myeloid-Lymphoid Leukemia Protein / Q000172:deficiency / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D019076:Transgenes / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D006657:Histones; D018398:Homeodomain Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D014212:Tretinoin; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse; C510860:Kmt2d protein, mouse; D008239:Lysine
keywords: Bivalent promoters; Epigenetics; Epigenome; Histone methylation; Kmt2; Polycomb group; Trithorax group