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Open Access 01-12-2017 | Research

Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration

Authors: Lei Zhao, Jun Li, Yingmei Fu, Mengxue Zhang, Bowen Wang, Jonathan Ouellette, Pawan K. Shahi, Bikash R. Pattnaik, Jyoti J. Watters, Wai T. Wong, Lian-Wang Guo

Published in: Journal of Neuroinflammation | Issue 1/2017

Abstract

Background

The bromodomain and extraterminal domain (BET) family proteins (BET2, BET3, and BET4) “read” (bind) histone acetylation marks via two distinct bromodomains (Brom1 and Brom2) facilitating transcriptional activation. These epigenetic “readers” play crucial roles in pathogenic processes such as inflammation. The role of BETs in influencing the degenerative process in the retina is however unknown.

Methods

We employed the rd10 mouse model (Pde6b ^rd10 mutation) of retinitis pigmentosa (RP) to examine the involvement of BET proteins in retinal neurodegeneration.

Results

Inhibition of BET activity by intravitreal delivery of JQ1, a BET-specific inhibitor binding both Brom1 and Brom2, ameliorated photoreceptor degeneration and improved electroretinographic function. Rescue effects of JQ1 were related to the suppression of retinal microglial activation in vivo, as determined by decreased immunostaining of activation markers (IBA1, CD68, TSPO) and messenger RNA (mRNA) levels of inflammatory cytokines in microglia purified from rd10 retinas. JQ1 pre-treatment also suppressed microglial activation in vitro, decreasing microglial proliferation, migration, and mRNA expression of inflammatory cytokines (TNFα, MCP-1, IL-1β, IL-6, and RANTES). Expression of BET2, but not BET3 and BET4, was significantly elevated during photoreceptor degeneration at postnatal day (PN)24 in retinas of rd10 mice relative to age-matched wild-type controls. siRNA knockdown of BET2 but not BET4, and the inhibitor of Brom2 (RVX208) but not of Brom1 (Olinone), decreased microglial activation.

Conclusions

These findings indicate that BET inhibition rescues photoreceptor degeneration likely via the suppression of microglial activation and implicates BET interference as a potential therapeutic strategy for the treatment of degenerative retinal diseases.

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Title: Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration
Authors: Lei Zhao
Jun Li
Yingmei Fu
Mengxue Zhang
Bowen Wang
Jonathan Ouellette
Pawan K. Shahi
Bikash R. Pattnaik
Jyoti J. Watters
Wai T. Wong
Lian-Wang Guo
Publication date: 01-12-2017
Publisher: BioMed Central
Published in: Journal of Neuroinflammation / Issue 1/2017
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-016-0775-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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