The role of the TET-dependent DNA demethylation pathway in photoreceptor development and pathology

Disturbances in the development and function of photoreceptors invariably lead to blindness, which can have devastating consequences on a person's normal life. Understanding the mechanisms responsible for the development and function of photoreceptors allows us to restore visual function by imparting activity to abnormal photoreceptors or via the regeneration of lost photoreceptors. While significant progress has been made in understanding the signaling cascades that regulate photoreceptor development and function, the contribution of epigenetic mechanisms to these processes is poorly understood. The objective of this study was to explore the role of the TET-dependent DNA demethylation pathway in photoreceptor development and function. We found that genetic ablation of the TET family (Tet1, Tet2, and Tet3) prevents the DNA demethylation process during the differentiation of RPCs into photoreceptors. Preservation of methylation in the promoters of genes necessary for the development and function of photoreceptors significantly reduces their expression. All these events interfere with the development of photoreceptor outer segments and synapses, depriving the retina of functioning rod and cone photoreceptors. Over time, the number of such underdeveloped nonfunctional photoreceptors decreases, leading to retinal dystrophy.