title: High-glucose-induced CARM1 expression regulates apoptosis of human retinal pigment epithelial cells via histone 3 arginine 17 dimethylation: role in diabetic retinopathy.
abstract: Hyperglycemia-induced apoptosis of retinal pigment epithelial (RPE) cells is considered to be involved in the progression of diabetic retinopathy. Histone arginine methylation catalyzed by protein arginine methyltransferases (PRMTs) has emerged as an important histone modification involved in gene regulation. However, the role of PRMTs in diabetic retinopathy has not been elucidated. Here, we found that expression of coactivator-associated arginine methyltransferase 1 (CARM1; also known as PRMT4) was increased in the high-glucose treated human RPE cell line ARPE-19 and in the RPE layer of streptozotocin-treated rats. In addition, high-glucose induced apoptosis in ARPE-19 cells. To determine the function of CARM1 on RPE cell apoptosis, we performed gain- and loss-of-function studies. CARM1 overexpression increased apoptosis of RPE cells. In contrast, silencing of CARM1 expression by siRNA and pharmacological inhibition of CARM1 activity abolished high-glucose-induced RPE cell apoptosis. Furthermore, we found that inhibition of histone 3 arginine 17 (H3R17) asymmetric dimethylation attenuates both CARM1- and high-glucose-induced apoptosis in RPE cells. Together, these results show that high-glucose-induced CARM1 expression increases RPE cell apoptosis via H3R17 asymmetric dimethylation. Strategies to reduce CARM1 expression or enzymatic activity could be used to prevent apoptosis of RPE cells in the progression of diabetic retinopathy.
authors: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors: Dong-il
authors: DI
authors: Kim
authors: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors: Min-jung
authors: MJ
authors: Park
authors: Metabolism and Functionality Research Group, R & D Division, World Institute of Kimchi, 503-360, Republic of Korea.
authors: Seul-ki
authors: SK
authors: Lim
authors: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors: Joo-hee
authors: JH
authors: Choi
authors: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors: Jong-choon
authors: JC
authors: Kim
authors: College of Veterinary Medicine, Seoul National University, Seoul 151-741, Republic of Korea.
authors: Ho-jae
authors: HJ
authors: Han
authors: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560 064, India.
authors: Tapas K
authors: TK
authors: Kundu
authors: Korea Basic Science Institute, Gwangju Center at Chonnam National University, Gwangju 500-757, Republic of Korea.
authors: Jae-il
authors: JI
authors: Park
authors: Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 501-757, Republic of Korea.
authors: Kyung-chul
authors: KC
authors: Yoon
authors: Department of Ophthalmology, Chonnam National University Medical School and Hospital, Gwangju 501-757, Republic of Korea.
authors: Sang-woo
authors: SW
authors: Park
authors: Department of Physiology, Chonnam National University Medical School and Hospital, Gwangju 501-757, Republic of Korea.
authors: Jong-sung
authors: JS
authors: Park
authors: Department of Food and Nutrition, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: yrhuh@jnu.ac.kr.
authors: Young-ran
authors: YR
authors: Heo
authors: College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: parksh@chonnam.ac.kr.
authors: Soo-hyun
authors: SH
authors: Park
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001120:Arginine / Q000378:metabolism*; D002460:Cell Line; D003930:Diabetic Retinopathy / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006657:Histones / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008297:Male; D008745:Methylation / Q000187:drug effects; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000473:pathology*
chemical_list: D006657:Histones; D001120:Arginine; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D005947:Glucose
keywords: Apoptosis; CARM1; Coactivator-associated arginine methyltransferase 1; Diabetic retinopathy; Protein arginine methyltransferase; Retinal pigment epithelial cells