Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration
作者： Lei Zhao , Jun Li , Yingmei Fu , Mengxue Zhang , Bowen Wang
DOI: 10.1186/S12974-016-0775-4
关键词: Neurodegeneration 、 PDE6B 、 Retinal 、 Proinflammatory cytokine 、 Retinitis pigmentosa 、 Retina 、 Cell biology 、 Bromodomain 、 Retinal degeneration 、 Biology 、 Immunology
摘要: The bromodomain and extraterminal domain (BET) family proteins (BET2, BET3, BET4) “read” (bind) histone acetylation marks via two distinct bromodomains (Brom1 Brom2) facilitating transcriptional activation. These epigenetic “readers” play crucial roles in pathogenic processes such as inflammation. role of BETs influencing the degenerative process retina is however unknown. We employed rd10 mouse model (Pde6b rd10 mutation) retinitis pigmentosa (RP) to examine involvement BET retinal neurodegeneration. Inhibition activity by intravitreal delivery JQ1, a BET-specific inhibitor binding both Brom1 Brom2, ameliorated photoreceptor degeneration improved electroretinographic function. Rescue effects JQ1 were related suppression microglial activation vivo, determined decreased immunostaining markers (IBA1, CD68, TSPO) messenger RNA (mRNA) levels inflammatory cytokines microglia purified from retinas. pre-treatment also suppressed vitro, decreasing proliferation, migration, mRNA expression (TNFα, MCP-1, IL-1β, IL-6, RANTES). Expression BET2, but not BET3 BET4, was significantly elevated during at postnatal day (PN)24 retinas mice relative age-matched wild-type controls. siRNA knockdown BET2 Brom2 (RVX208) (Olinone), findings indicate that inhibition rescues likely implicates interference potential therapeutic strategy for treatment diseases.
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