dLKR/SDH regulates hormone-mediated histone arginine methylation and transcription of cell death genes.
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.
Cakouros
Dimitrios
D
Hanson Institute, Institute of Medical and Veterinary Science, Adelaide SA 5000, Australia.
Mills
Kathryn
K
Denton
Donna
D
Paterson
Alicia
A
Daish
Tasman
T
Kumar
Sharad
S
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
D029721:Drosophila Proteins; D006657:Histones; D011987:Receptors, Steroid; C055469:ecdysone receptor; D004440:Ecdysone; D001120:Arginine; D012443:Saccharopine Dehydrogenases; D020169:Caspases; C118731:dronc protein, Drosophila