title: MEP50/PRMT5 Reduces Gene Expression by Histone Arginine Methylation and this Is Reversed by PKCδ/p38δ Signaling.
abstract: Protein kinase C δ (PKCδ) and p38δ are key proteins in a cascade that stimulates keratinocyte differentiation. This cascade activates transcription of involucrin (hINV) and other genes associated with differentiation. Protein arginine methyltransferase 5 (PRMT5) is an arginine methyltransferase that symmetrically dimethylates arginine residues. This protein interacts with a cofactor, methylosome protein 50 (MEP50), and symmetrically dimethylates arginine eight of histone 3 (H3R8me2s) and arginine three of histone 4 (H4R3me2s) to silence gene expression. We use the hINV gene as a tool to understand the relationship between PKCδ/p38δ and PRMT5/MEP50 signaling. MEP50 suppresses hINV mRNA level and promoter activity. This is associated with increased arginine dimethylation of hINV gene-associated H3/H4. We further show that the PKCδ/p38δ keratinocyte differentiation cascade reduces PRMT5 and MEP50 expression, association with the hINV gene promoter, and H3R8me2s and H4R2me2s formation. We propose that PRMT5/MEP50-dependent methylation is an epigenetic mechanism that assists in silencing of hINV expression, and that PKCδ signaling activates gene expression by directly activating transcription and by suppressing PRMT5/MEP50-dependent arginine dimethylation of promoter-associated histones. This is an example of crosstalk between PKCδ/p38δ signaling and PRMT5/MEP50 epigenetic silencing.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Kamalika
authors.initials: K
authors.lastname: Saha
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Adhikary
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Department of Obstetrics and Gynecology, University of Maryland School of Medicine, Baltimore, Maryland, USA; Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA. Electronic address: reckert@umaryland.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Eckert
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D008745:Methylation; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics* / Q000378:metabolism; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D011484:Protein-Arginine N-Methyltransferases; C077013:PRMT2 protein, human; C400529:PRMT5 protein, human; C478359:WDR77 protein, human; D014157:Transcription Factors