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Evgenya Popova, Carolina Pinzon-Guzman, Anna Salzberg, Arthur Berg, Samuel Shaomin Zhang, Colin J Barnstable; Lysine demethylase 1 is required for mouse rod photoreceptor development.. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4998.
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© ARVO (1962-2015); The Authors (2016-present)
The involvement of epigenetic factors in retinogenesis is poorly understood. Growing evidence shows that posttraslational modification of histones is a dynamic process that correlates with gene expression. We have previously shown that inactivation of many developmental genes during rod photoreceptor maturation correlates with decrease of an active epigenetic mark H3K4me2 on the transcriptional start site and body of these genes. The purpose of this study is to understand what histone modification enzymes may be involved in regulating the epigenetic status of genes during retina development and the role of this status in controlling rod photoreceptor maturation.
Animal use was in accordance with ARVO/IACUC guidelines. Whole retina explants were isolated from C57BL/6j mice pups at postnatal day 1 and were cultured individually in 1ml of media as a control or with LSD1inhibitors for 24h, 4 days or 8 days. Illumina MouseRef8 v2.0 Expression BeadChip (BD-202-0202) was processed starting with 500ng of template and using standard Illumina Total Prep protocol.
One of the H3K4me2/1 histone demethylases, LSD1 is expressed in retinal postmitotic cells at the peak of rod photoreceptor differentiation. Pharmacological inhibition of LSD1in retinal explants cultured from PN1 to PN8 blocks rod photoreceptor development. LSD1 suppression abolishes decreases in H3K4me2 accumulation at the promoter and gene body of developmental genes that are normally downregulated at this developmental stage. Under LSD1 inhibition retinal cells keep high levels of expression of the genes responsible for cell cycle progression, progenitor and cell fate specification. Additionally LSD1 inhibition arrest normal retina development by increasing expression of the genes specific for non-rod cell types such as cone photoreceptors or bipolar cells, while keeping rod-specific genes at low transcriptional levels.
These findings suggest that LSD1is required for: a) developmental genes to withdraw in postmitotic retina progenitors; b) inhibition of non-rod genes in rod photoreceptor during maturation. LSD1 function is necessary for rod photoreceptor formation and histone methylation status of the genes involved in retina development is important for retinogenesis.
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