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The DNA methylation inhibitor RG108 protects against noise-induced hearing loss

BACKGROUND: Noise-induced hearing loss represents a commonly diagnosed type of hearing disability, severely impacting the quality of life of individuals. The current work is aimed at assessing the effects of DNA methylation on noise-induced hearing loss. METHODS: Blocking DNA methyltransferase 1 (DN...

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Autores principales: Zheng, Zhiwei, Zeng, Shan, Liu, Chang, Li, Wen, Zhao, Liping, Cai, Chengfu, Nie, Guohui, He, Yingzi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Netherlands 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490244/
https://www.ncbi.nlm.nih.gov/pubmed/33723744
http://dx.doi.org/10.1007/s10565-021-09596-y
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author Zheng, Zhiwei
Zeng, Shan
Liu, Chang
Li, Wen
Zhao, Liping
Cai, Chengfu
Nie, Guohui
He, Yingzi
author_facet Zheng, Zhiwei
Zeng, Shan
Liu, Chang
Li, Wen
Zhao, Liping
Cai, Chengfu
Nie, Guohui
He, Yingzi
author_sort Zheng, Zhiwei
collection PubMed
description BACKGROUND: Noise-induced hearing loss represents a commonly diagnosed type of hearing disability, severely impacting the quality of life of individuals. The current work is aimed at assessing the effects of DNA methylation on noise-induced hearing loss. METHODS: Blocking DNA methyltransferase 1 (DNMT1) activity with a selective inhibitor RG108 or silencing DNMT1 with siRNA was used in this study. Auditory brainstem responses were measured at baseline and 2 days after trauma in mice to assess auditory functions. Whole-mount immunofluorescent staining and confocal microcopy of mouse inner ear specimens were performed to analyze noise-induced damage in cochleae and the auditory nerve at 2 days after noise exposure. RESULTS: The results showed that noise exposure caused threshold elevation of auditory brainstem responses and cochlear hair cell loss. Whole-mount cochlea staining revealed a reduction in the density of auditory ribbon synapses between inner hair cells and spiral ganglion neurons. Inhibition of DNA methyltransferase activity via a non-nucleoside specific pharmacological inhibitor, RG108, or silencing of DNA methyltransferase-1 with siRNA significantly attenuated ABR threshold elevation, hair cell damage, and the loss of auditory synapses. CONCLUSIONS: This study suggests that inhibition of DNMT1 ameliorates noise-induced hearing loss and indicates that DNMT1 may be a promising therapeutic target. GRAPHICAL ABSTRACT: [Figure: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10565-021-09596-y.
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spelling pubmed-84902442021-10-15 The DNA methylation inhibitor RG108 protects against noise-induced hearing loss Zheng, Zhiwei Zeng, Shan Liu, Chang Li, Wen Zhao, Liping Cai, Chengfu Nie, Guohui He, Yingzi Cell Biol Toxicol Original Article BACKGROUND: Noise-induced hearing loss represents a commonly diagnosed type of hearing disability, severely impacting the quality of life of individuals. The current work is aimed at assessing the effects of DNA methylation on noise-induced hearing loss. METHODS: Blocking DNA methyltransferase 1 (DNMT1) activity with a selective inhibitor RG108 or silencing DNMT1 with siRNA was used in this study. Auditory brainstem responses were measured at baseline and 2 days after trauma in mice to assess auditory functions. Whole-mount immunofluorescent staining and confocal microcopy of mouse inner ear specimens were performed to analyze noise-induced damage in cochleae and the auditory nerve at 2 days after noise exposure. RESULTS: The results showed that noise exposure caused threshold elevation of auditory brainstem responses and cochlear hair cell loss. Whole-mount cochlea staining revealed a reduction in the density of auditory ribbon synapses between inner hair cells and spiral ganglion neurons. Inhibition of DNA methyltransferase activity via a non-nucleoside specific pharmacological inhibitor, RG108, or silencing of DNA methyltransferase-1 with siRNA significantly attenuated ABR threshold elevation, hair cell damage, and the loss of auditory synapses. CONCLUSIONS: This study suggests that inhibition of DNMT1 ameliorates noise-induced hearing loss and indicates that DNMT1 may be a promising therapeutic target. GRAPHICAL ABSTRACT: [Figure: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10565-021-09596-y. Springer Netherlands 2021-03-15 2021 /pmc/articles/PMC8490244/ /pubmed/33723744 http://dx.doi.org/10.1007/s10565-021-09596-y Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Zheng, Zhiwei
Zeng, Shan
Liu, Chang
Li, Wen
Zhao, Liping
Cai, Chengfu
Nie, Guohui
He, Yingzi
The DNA methylation inhibitor RG108 protects against noise-induced hearing loss
title The DNA methylation inhibitor RG108 protects against noise-induced hearing loss
title_full The DNA methylation inhibitor RG108 protects against noise-induced hearing loss
title_fullStr The DNA methylation inhibitor RG108 protects against noise-induced hearing loss
title_full_unstemmed The DNA methylation inhibitor RG108 protects against noise-induced hearing loss
title_short The DNA methylation inhibitor RG108 protects against noise-induced hearing loss
title_sort dna methylation inhibitor rg108 protects against noise-induced hearing loss
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490244/
https://www.ncbi.nlm.nih.gov/pubmed/33723744
http://dx.doi.org/10.1007/s10565-021-09596-y
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