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Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes

Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Heterochromatin, a compact and transcriptional inert chromatin structure, has been recent...

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Autores principales: Gong, Lili, Liu, Fangyuan, Xiong, Zhen, Qi, Ruili, Luo, Zhongwen, Gong, Xiaodong, Nie, Qian, Sun, Qian, Liu, Yun-Fei, Qing, Wenjie, Wang, Ling, Zhang, Lan, Tang, Xiangcheng, Huang, Shan, Li, Gen, Ouyang, Hong, Xiang, Mengqing, Nguyen, Quan Dong, Liu, Yizhi, Li, David Wan-Cheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924883/
https://www.ncbi.nlm.nih.gov/pubmed/29622681
http://dx.doi.org/10.1073/pnas.1715237115
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author Gong, Lili
Liu, Fangyuan
Xiong, Zhen
Qi, Ruili
Luo, Zhongwen
Gong, Xiaodong
Nie, Qian
Sun, Qian
Liu, Yun-Fei
Qing, Wenjie
Wang, Ling
Zhang, Lan
Tang, Xiangcheng
Huang, Shan
Li, Gen
Ouyang, Hong
Xiang, Mengqing
Nguyen, Quan Dong
Liu, Yizhi
Li, David Wan-Cheng
author_facet Gong, Lili
Liu, Fangyuan
Xiong, Zhen
Qi, Ruili
Luo, Zhongwen
Gong, Xiaodong
Nie, Qian
Sun, Qian
Liu, Yun-Fei
Qing, Wenjie
Wang, Ling
Zhang, Lan
Tang, Xiangcheng
Huang, Shan
Li, Gen
Ouyang, Hong
Xiang, Mengqing
Nguyen, Quan Dong
Liu, Yizhi
Li, David Wan-Cheng
author_sort Gong, Lili
collection PubMed
description Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Heterochromatin, a compact and transcriptional inert chromatin structure, has been recently shown to be dynamically regulated in response to stress stimuli. The functional mechanism of heterochromatin on OS exposure is unclear, however. Here we show that OS increases heterochromatin formation both in vivo and in vitro, which is essential for protecting RPE cells from oxidative damage. Mechanistically, OS-induced heterochromatin selectively accumulates at p53-regulated proapoptotic target promoters and inhibits their transcription. Furthermore, OS-induced desumoylation of p53 promotes p53–heterochromatin interaction and regulates p53 promoter selection, resulting in the locus-specific recruitment of heterochromatin and transcription repression. Together, our findings demonstrate a protective function of OS-induced heterochromatin formation in which p53 desumoylation-guided promoter selection and subsequent heterochromatin recruitment play a critical role. We propose that targeting heterochromatin provides a plausible therapeutic strategy for the treatment of AMD.
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spelling pubmed-59248832018-04-30 Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes Gong, Lili Liu, Fangyuan Xiong, Zhen Qi, Ruili Luo, Zhongwen Gong, Xiaodong Nie, Qian Sun, Qian Liu, Yun-Fei Qing, Wenjie Wang, Ling Zhang, Lan Tang, Xiangcheng Huang, Shan Li, Gen Ouyang, Hong Xiang, Mengqing Nguyen, Quan Dong Liu, Yizhi Li, David Wan-Cheng Proc Natl Acad Sci U S A PNAS Plus Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Heterochromatin, a compact and transcriptional inert chromatin structure, has been recently shown to be dynamically regulated in response to stress stimuli. The functional mechanism of heterochromatin on OS exposure is unclear, however. Here we show that OS increases heterochromatin formation both in vivo and in vitro, which is essential for protecting RPE cells from oxidative damage. Mechanistically, OS-induced heterochromatin selectively accumulates at p53-regulated proapoptotic target promoters and inhibits their transcription. Furthermore, OS-induced desumoylation of p53 promotes p53–heterochromatin interaction and regulates p53 promoter selection, resulting in the locus-specific recruitment of heterochromatin and transcription repression. Together, our findings demonstrate a protective function of OS-induced heterochromatin formation in which p53 desumoylation-guided promoter selection and subsequent heterochromatin recruitment play a critical role. We propose that targeting heterochromatin provides a plausible therapeutic strategy for the treatment of AMD. National Academy of Sciences 2018-04-24 2018-04-05 /pmc/articles/PMC5924883/ /pubmed/29622681 http://dx.doi.org/10.1073/pnas.1715237115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Gong, Lili
Liu, Fangyuan
Xiong, Zhen
Qi, Ruili
Luo, Zhongwen
Gong, Xiaodong
Nie, Qian
Sun, Qian
Liu, Yun-Fei
Qing, Wenjie
Wang, Ling
Zhang, Lan
Tang, Xiangcheng
Huang, Shan
Li, Gen
Ouyang, Hong
Xiang, Mengqing
Nguyen, Quan Dong
Liu, Yizhi
Li, David Wan-Cheng
Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes
title Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes
title_full Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes
title_fullStr Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes
title_full_unstemmed Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes
title_short Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes
title_sort heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924883/
https://www.ncbi.nlm.nih.gov/pubmed/29622681
http://dx.doi.org/10.1073/pnas.1715237115
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