Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783318609773199360 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5924883 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT gonglili heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT liufangyuan heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT xiongzhen heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT qiruili heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT luozhongwen heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT gongxiaodong heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT nieqian heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT sunqian heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT liuyunfei heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT qingwenjie heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT wangling heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT zhanglan heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT tangxiangcheng heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT huangshan heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT ligen heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT ouyanghong heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT xiangmengqing heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT nguyenquandong heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT liuyizhi heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes AT lidavidwancheng heterochromatinprotectsretinalpigmentepitheliumcellsfromoxidativedamagebysilencingp53targetgenes |