An epigenetic light switch: How DNA demethylation in the retina shapes our vision

What is it about?

This study revealed the unique role of epigenetics in the development and function of rod and cone photoreceptors, which are light-sensing retinal neurons and the loss of which leads to blindness. The study shows that DNA methylation, as an epigenetic mechanism, controls the activity of virtually all genes that regulate photoreceptor development and function: DNA methylation suppresses the activity of these genes in retinal progenitor cells (RPCs), while active DNA demethylation controlled by the Ten-Eleven Translocation (TET) family of enzymes is required for the differentiation of RPCs into mature and functional rods and cones. By genetically inactivating TET enzymes in RPCs, the authors observed impaired rod and cone photoreceptor specification and maturation, resulting in the underdevelopment or complete absence of light-sensing structures and neuronal synaptic termini, retinal disorganization, and, ultimately, blindness. Furthermore, to a lesser extent than in photoreceptors, but significant enough to be detectable, the lack of TET activity affects the development of other retinal cell types, highlighting the broad importance of DNA demethylation for retinal health and function.

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Photo by Artyom Korshunov on Unsplash

Photo by Artyom Korshunov on Unsplash

Why is it important?

There are many genes that regulate the specification of photoreceptors from RPCs and their subsequent maturation into functional cones and rods. Impaired activity of these genes as a result of mutations leads to various inherited retinal diseases (IRD), such as retinitis pigmentosa, cone and cone-rod dystrophy, congenital stationary night blindness, and Leber congenital amaurosis, from which millions of people in the US and the world go blind, many of whom are very young. Thanks to this study, we now know that DNA demethylation controlled by TET enzymes regulates the activity of virtually all of these genes. Thus, many IRD may turn out to be not only genetic but also epigenetic diseases, which can significantly affect the diagnosis and treatment of IRD. The time has also come to look beyond merely halting the progression of IRD and to work toward restoring visual function by regenerating lost photoreceptors. While significant advances have been made in this field, protocols that lead to the generation of developed and functional rods and cones have yet to be created. The difficulties in differentiating photoreceptors may be due to the failure to consider the DNA demethylation process. Thus, understanding the contribution of DNA demethylation controlled by TET enzymes to photoreceptor development and function is also important for developing approaches to regenerate these neurons.