Abstract
BackgroundThe 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.MethodsWe employed the rd10 mouse model (Pde6brd10 mutation) of retinitis pigmentosa (RP) to examine the involvement of BET proteins in retinal neurodegeneration.ResultsInhibition 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.ConclusionsThese 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.
Highlights
The bromodomain and extraterminal domain (BET) family proteins (BET2, BET3, and BET4) “read” histone acetylation marks via two distinct bromodomains (Brom1 and Brom2) facilitating transcriptional activation
Eyeballs were collected at PN18, PN21, PN24, PN27, and PN30 for the preparation of retinal sections, and photoreceptor numbers were counted in the outer nuclear layer (ONL) (Fig. 1a, Additional file 1: Figure S1)
Inasmuch as microglial activation plays a crucial role in photoreceptor degeneration, as recently demonstrated in rd10 mice [6, 7], our results suggest that epigenetic interference targeting BET proteins may open a new avenue to protect photoreceptors via effective suppression of microglial activation
Summary
The bromodomain and extraterminal domain (BET) family proteins (BET2, BET3, and BET4) “read” (bind) histone acetylation marks via two distinct bromodomains (Brom and Brom2) facilitating transcriptional activation. These epigenetic “readers” play crucial roles in pathogenic processes such as inflammation. A report using the rd model discovered a positive feedback mechanism whereby activated microglia migrate to and phagocytose non-apoptotic photo-receptors and become even more activated, profoundly accelerating the loss of both non-apoptotic and apoptotic photoreceptors [7]. Pathogenic microglial activation is associated with photoreceptor loss in RP and age-related macular degeneration and diabetic retinopathy in animal models and human patients [8]. Poor understanding of the molecular mechanism(s) underlying microglial activation, in the retina, poses a major barrier to applying this strategy [8]
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