MEP50/PRMT5 Reduces Gene Expression by Histone Arginine Methylation and this Is Reversed by PKCδ/p38δ Signaling.
MEP50/PRMT5 Reduces Gene Expression by Histone Arginine Methylation and this Is Reversed by PKCδ/p38δ Signaling.
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DOI：
10.1038/jid.2015.400
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Eckert RL
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文献类型：
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作者：
Saha K;Adhikary G;Eckert RL
PKCδ和p38δ是刺激角质形成细胞分化的级联反应中的关键蛋白。该级联激活外皮蛋白（hINV）和其他与分化相关的基因的转录。蛋白质精氨酸甲基转移酶5（PRMT 5）是一种精氨酸甲基转移酶，其对称地使精氨酸残基二甲基化。该蛋白与辅因子MEP 50相互作用，并对称地二甲基化组蛋白3的精氨酸8（H3 R8 me 2s）和组蛋白4的精氨酸3（H4 R3 me 2s）以沉默基因表达。我们使用involucrin基因作为工具来了解PKCδ/p38δ和PRMT 5/MEP 50信号转导之间的关系。MEP 50抑制hINV mRNA水平和启动子活性。这与hINV基因相关H3/H4的精氨酸二甲基化增加有关。我们进一步表明，PKCδ/p38δ角质形成细胞分化级联减少PRMT 5和MEP 50表达，与hINV基因启动子相关，以及H3 R8 me 2s和H4 R2 me 2s形成。我们认为PRMT 5/MEP 50依赖性甲基化是一种有助于沉默hINV表达的表观遗传机制，PKCδ信号通过直接激活转录和抑制启动子相关组蛋白的PRMT 5/MEP 50依赖性精氨酸二甲基化来激活基因表达。这是PKCδ/p38δ信号传导和PRMT 5/MEP 50表观遗传沉默之间串扰的实例。
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, MEP50, and symmetrically dimethylates arginine eight of histone 3 (H3R8me2s) and arginine three of histone 4 (H4R3me2s) to silence gene expression. We use the involucrin 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.