title: Photoreceptor protection via blockade of BET epigenetic readers in a murine model of inherited retinal degeneration.
abstract: 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.
  
  
  
  We employed the rd10 mouse model (Pde6brd10mutation) of retinitis pigmentosa (RP) to examine the involvement of BET proteins in retinal neurodegeneration.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.|Department of Ophthalmology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China.|Department of Ophthalmology, The 3rd People's Hospital of Dalian, Dalian, 116033, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.|Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, 600 Wanping Nan Road, Shanghai, 200030, People's Republic of China.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
authors.forename: Mengxue
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA.
authors.forename: Bowen
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison, WI, 53706, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Ouellette
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, WI, USA.|Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA.
authors.forename: Pawan K
authors.initials: PK
authors.lastname: Shahi
authors.affiliation: Department of Pediatrics, University of Wisconsin, Madison, WI, USA.|McPherson Eye Research Institute, University of Wisconsin, Madison, WI, 53705, USA.|Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI, USA.
authors.forename: Bikash R
authors.initials: BR
authors.lastname: Pattnaik
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin, Madison, WI, 53706, USA.
authors.forename: Jyoti J
authors.initials: JJ
authors.lastname: Watters
authors.affiliation: Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Wai T
authors.initials: WT
authors.lastname: Wong
authors.affiliation: Department of Surgery, 5151 Wisconsin Institute for Medical Research, University of Wisconsin School of Medicine and Public Health, Madison, WI, 53705, USA. guo@surgery.wisc.edu.|McPherson Eye Research Institute, University of Wisconsin, Madison, WI, 53705, USA. guo@surgery.wisc.edu.
authors.forename: Lian-Wang
authors.initials: LW
authors.lastname: Guo
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000172:deficiency* / Q000235:genetics; D010786:Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000172:deficiency* / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: C486765:Dner protein, mouse; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface
keywords: Bromodomain and extraterminal domain (BET) proteins; Epigenetic readers; JQ1; Microglial activation; Retinal degeneration; rd10 mice