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

Bikash Pattnaik // Publications // Jan 19 2017

PubMed ID: 28103888

Author(s): Zhao L, Li J, Fu Y, Zhang M, Wang B, Ouellette J, Shahi PK, Pattnaik BR, Watters JJ, Wong WT, Guo LW. Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration. J Neuroinflammation. 2017 Jan 19;14(1):14. doi: 10.1186/s12974-016-0775-4. PMID 28103888

Journal: Journal Of Neuroinflammation, Volume 14, Issue 1, 01 2017

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.