title: dLKR/SDH regulates hormone-mediated histone arginine methylation and transcription of cell death genes.
abstract: The sequential modifications of histones form the basis of the histone code that translates into either gene activation or repression. Nuclear receptors recruit a cohort of histone-modifying enzymes in response to ligand binding and regulate proliferation, differentiation, and cell death. In Drosophila melanogaster, the steroid hormone ecdysone binds its heterodimeric receptor ecdysone receptor/ultraspiracle to spatiotemporally regulate the transcription of several genes. In this study, we identify a novel cofactor, Drosophila lysine ketoglutarate reductase (dLKR)/saccharopine dehydrogenase (SDH), that is involved in ecdysone-mediated transcription. dLKR/SDH binds histones H3 and H4 and suppresses ecdysone-mediated transcription of cell death genes by inhibiting histone H3R17me2 mediated by the Drosophila arginine methyl transferase CARMER. Our data suggest that the dynamic recruitment of dLKR/SDH to ecdysone-regulated gene promoters controls the timing of hormone-induced gene expression. In the absence of dLKR/SDH, histone methylation occurs prematurely, resulting in enhanced gene activation. Consistent with these observations, the loss of dLKR/SDH in Drosophila enhances hormone-regulated gene expression, affecting the developmental timing of gene activation.
authors.affiliation: Hanson Institute, Institute of Medical and Veterinary Science, Adelaide SA 5000, Australia.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Cakouros
authors.forename: Kathryn
authors.initials: K
authors.lastname: Mills
authors.forename: Donna
authors.initials: D
authors.lastname: Denton
authors.forename: Alicia
authors.initials: A
authors.lastname: Paterson
authors.forename: Tasman
authors.initials: T
authors.lastname: Daish
authors.forename: Sharad
authors.initials: S
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D001665:Binding Sites; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology / Q000196:embryology / Q000201:enzymology* / Q000235:genetics*; D004440:Ecdysone / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017344:Genes, Insect; D006657:Histones / Q000378:metabolism*; D007700:Kinetics; D008745:Methylation / Q000187:drug effects; D008957:Models, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034622:RNA Interference; D011987:Receptors, Steroid / Q000378:metabolism; D012443:Saccharopine Dehydrogenases / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects*; D015533:Transcriptional Activation
chemical_list: D029721:Drosophila Proteins; D006657:Histones; D011987:Receptors, Steroid; C055469:ecdysone receptor; D004440:Ecdysone; D001120:Arginine; D012443:Saccharopine Dehydrogenases; D020169:Caspases; C118731:dronc protein, Drosophila