MEP50/PRMT5 Reduces Gene Expression by Histone Arginine Methylation and this Is Reversed by PKC?/p38? Signaling.

ABSTRACT: Protein kinase C ? (PKC?) and p38? 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 PKC?/p38? 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 PKC?/p38? 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 PKC? 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 PKC?/p38? signaling and PRMT5/MEP50 epigenetic silencing.

SUBMITTER: Saha K 

PROVIDER: S-EPMC4899982 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature