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I. O. Nasonkin, D. Hambright, R. Rachel, M. Jamrich, G. Oliver, R. Jaenisch, R. Fariss, A. Swaroop; Role of Epigenetics (DNA Methylation) in Retinal Differentiation. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4141.
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NA methylation is essential for development and differentiation, and is orchestrated in all mammals by three DNA methyltransferases. Dnmt3a and Dnmt3b are responsible for de novo methylation of DNA, while Dnmt1 maintains the established methylation patterns in dividing cells. A well-studied developmental effect of DNA methylation is stable silencing of gene expression. Accumulating evidence suggests that site-specific DNA methylation may be a key mechanism for generation and maintenance of cell-type and tissue-specific gene expression. We hypothesize that retinal cell fate specification and differentiation is influenced by such epigenetic mechanisms.
A series of conditional eye-specific knockouts of the three Dnmts are being generated in mice using Rx-Cre and Six3-Cre driver lines. Histological changes in eyes of Dnmt1 conditional knockout mice were evaluated by light and electron microscopy using development stages from early post-natal through adult. Confocal immunlocalization studies were also performed on retinal sections using cell-specific antibodies to photoreceptors, RPE and Muller cells, and second order neurons.
Severe morphological changes were observed in the retina and RPE of Dnmt1 knockout animals. These pathologic changes included severely shortened or absent photoreceptor outer segments, retinal folding and rosette formation, regions of attenuated RPE and abnormalities in retinal lamination.
Our studies provide the first evidence of Dnmt-mediated epigenetic mechanisms guiding retinal development.
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