title: Impaired removal of H3K4 methylation affects cell fate determination and gene transcription.
abstract: Methylation of histone 3 lysine 4 (H3K4) is largely associated with promoters and enhancers of actively transcribed genes and is finely regulated during development by the action of histone methyltransferases and demethylases. H3K4me3 demethylases of the KDM5 family have been previously implicated in development, but how the regulation of H3K4me3 level controls developmental processes is not fully established. Here, we show that the H3K4 demethylase RBR-2, the unique member of the KDM5 family in C. elegans, acts cell-autonomously and in a catalytic-dependent manner to control vulva precursor cells fate acquisition, by promoting the LIN-12/Notch pathway. Using genome-wide approaches, we show that RBR-2 reduces the H3K4me3 level at transcription start sites (TSSs) and in regions upstream of the TSSs, and acts both as a transcription repressor and activator. Analysis of the lin-11 genetic locus, a direct RBR-2 target gene required for vulva precursor cell fate acquisition, shows that RBR-2 controls the epigenetic signature of the lin-11 vulva-specific enhancer and lin-11 expression, providing in vivo evidence that RBR-2 can positively regulate transcription and cell fate acquisition by controlling enhancer activity.
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen DK-2200, Denmark.|Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark.
authors: Yvonne C
authors: YC
authors: Lussi
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen DK-2200, Denmark.|Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark.
authors: Luca
authors: L
authors: Mariani
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen DK-2200, Denmark.|Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark.
authors: Carsten
authors: C
authors: Friis
authors: A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, Kuopio 70211, Finland.
authors: Juhani
authors: J
authors: Peltonen
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen DK-2200, Denmark.|Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark.
authors: Toshia R
authors: TR
authors: Myers
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen DK-2200, Denmark.
authors: Claudia
authors: C
authors: Krag
authors: A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, University of Eastern Finland, Kuopio 70211, Finland.
authors: Garry
authors: G
authors: Wong
authors: Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen DK-2200, Denmark lisa.salcini@bric.ku.dk.|Centre for Epigenetics, University of Copenhagen, Copenhagen DK-2200, Denmark.
authors: Anna Elisabetta
authors: 0000-0001-5828-2512
authors: AE
authors: Salcini
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D056485:Retinoblastoma-Binding Protein 2 / Q000235:genetics / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D006657:Histones; D018398:Homeodomain Proteins; C111267:Lin-11 protein, C elegans; C519283:RBR-2 protein, C elegans; D056485:Retinoblastoma-Binding Protein 2; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: C. elegans; Enhancer; Gene transcription; H3K4 methylation; KDM5; RBR-2; VPC differentiation