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Stephen P. Sugrue, Guoliang Xu, Yoichi Kato, Yufei Xu, Y. Geno Shi; Tet3 is an Essential Epigenetic factor for Eye development. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5589.
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© ARVO (1962-2015); The Authors (2016-present)
Epigenetic mechanisms in ocular tissue represent exciting new areas of research that will potentially open a new horizon for understanding eye development and eye-related diseases or disorders. However, it has been a challenge to characterize changes in epigenetic processes such as histone modification and DNA methylation that impact ophthalmic health and disease, mainly because no clear-cut epigenetic regulators have been identified to play an essential role in eye development or ocular disease. In this study, we aim to characterize the essential role and its mechanism of action of one of the newly identified epigenetic regulator TET family of DNA methylation hydroxylases, tet3, in eye formation and development.
We used Xenopus as a model organism to study the tet3 function and its mechanism of action in early eye development. This study involves morpholino gene inactivation, gene overexpression, DNA hydroxylase activity assay, functional rescue, embryo biology, domain deletion analysis and Chromatin immunoprecipitation approaches.
We show that tet3 is an active 5mC hydroxylase and a CXXC domain-containing CpG DNA-binding protein. Overexpression of the tet3 genes in the embryo cause a severe cyclopia and small cement gland of the animal. Conversely, depletion of tet3 in Xenopus embryos causes severe defects in eye formation that resemble eyeless phenotype. These tet3 depeltion defects are associated with the reduced expression of key developmental genes pax6, rx and six3 and inhibition of sonic hedgehog (shh) signaling pathway. Importantly, we show that both the CXXC domain and enzymatic activity of tet3 are critical for the regulation of targeted gene expression and eye development.
These findings highlights the critical roles of tet family proteins in eye development and shed significant light on the molecular mechanisms of tet3 functions in epigenetic regulation of eye-essential genes during early eye formation and development.
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