Endothelial transcriptome in response to pharmacological methyltransferase inhibition.
The enzymatic activities of protein methyltransferases serve to write covalent modifications on histone and non-histone proteins in the control of gene transcription. Here, we describe gene expression changes in human endothelial cells caused by treatment with methyltransferase inhibitors 7,7'-carbonylbis (azanediyl) bis(4-hydroxynaphthalene-2 -sulfonic acid (AMI-1) and disodium-2-(2,4,5,7- tetrabromo-3-oxido-6-oxoxanthen-9-yl) benzoate trihydrate (AMI-5). Deep sequencing of mRNA indicated robust change on transcription following AMI-5 treatment compared with AMI-1. Functional annotation analysis revealed that both compounds suppress the expression of genes associated with translational regulation, suggesting arginine methylation by protein arginine methyltransferases (PRMTs) could be associated with regulation of this pathway. Interestingly, AMI-5 but not AMI-1 was found to decrease methylation of H3 histones at lysine 4 and down-regulate gene expression associated with interleukin-6 (IL-6) and activator protein-1 (AP-1) signaling pathways. These results imply that inhibition of protein methylation by AMI-1 and AMI-5 can differentially regulate specific pathways with potential to interrupt pathological signaling in the vascular endothelium.
Epigenetics in Human Health & Disease Laboratory, Baker IDI Heart & Diabetes Institute, The Alfred Medical Research & Education Precinct, Melbourne, Victoria 3004 (Australia); Faculty of Medicine, Nursing & Health Sciences, Monash University, Victoria 3800 (Australia).
Jun
J
Okabe
Ana Z
AZ
Fernandez
Mark
M
Ziemann
Samuel T
ST
Keating
Aneta
A
Balcerczyk
Assam
A
El-Osta
D002478:Cells, Cultured; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004801:Eosine Yellowish-(YS) / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008745:Methylation; D009282:Naphthalenesulfonates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011484:Protein-Arginine N-Methyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction; D059467:Transcriptome / Q000187:drug effects; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
C535077:7,7'-carbonylbis(azanediyl) bis(4-hydroxynaphthalene-2-sulfonic acid; D004791:Enzyme Inhibitors; D006657:Histones; D015850:Interleukin-6; D009282:Naphthalenesulfonates; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014508:Urea; D011484:Protein-Arginine N-Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C540312:SETD7 protein, human; D004801:Eosine Yellowish-(YS)
RNA sequencing; Set7; arginine methyltransferases; epigenetics; inhibitors; protein methylation; transcriptome