Epigenetic regulation of clusterin/apolipoprotein J expression in retinal pigment epithelial cells.
Age-related macular degeneration (AMD) is the leading cause of blindness worldwide. AMD is characterized by the deposition of drusen aggregates under the retinal pigment epithelium (RPE). Clusterin/apo J, a multifunctional secreted chaperone, is one of the major proteins accumulating in drusen deposits. The regulation of clusterin expression is not well characterized but the promoter of clusterin contains a CpG-rich methylation domain. Since aging affects both DNA methylation and histone acetylation status, the epigenetic regulation might have an important role in clusterin/apo J expression. Our purpose was to elucidate whether the induction of DNA hypomethylation with 5-aza-2'-deoxycytidine (AZA) and histone hyperacetylation with trichostatin A (TSA) could affect the clusterin transcription, protein levels, and secretion in retinal pigment epithelial cells. We observed that both TSA and AZA treatments induced a prominent increase in the expression levels of clusterin mRNA and protein in ARPE-19 cells, as well as in the secretion of clusterin protein. Furthermore, valproic acid, an antiepileptic drug and a recently identified inhibitor of histone deacetylases (HDAC), induced a significant increase in clusterin protein expression and secretion in retinal pigment epithelial cells. HDAC inhibitors are characterized as inhibitors of angiogenesis, and clusterin as a complement inhibitor. Our results indicate that epigenetic factors regulate the clusterin expression of RPE cells and thus might affect the pathogenesis of AMD via the inhibition of angiogenesis and inflammation.
Suuronen
Tiina
T
Department of Neuroscience and Neurology, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland.
Nuutinen
Tapio
T
Ryhänen
Tuomas
T
Kaarniranta
Kai
K
Salminen
Antero
A
D002478:Cells, Cultured; D051152:Clusterin / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D004847:Epithelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D010857:Pigment Epithelium of Eye / Q000166:cytology / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology*
C495242:CLU protein, human; D051152:Clusterin