Genetic ablation of the TET family in retinal progenitor cells impairs photoreceptor development and leads to blindness

• 成果类型: Article
• 署名作者: Dvoriantchikova, Galina; Moulin, Chloe; Fleishaker, Michelle; Almeida, Vania; Pelaez, Daniel; Lam, Byron L.; Ivanov, Dmitry
• 署名单位: Bascom Palmer Eye Institute; University of Miami; University of Miami; University of Miami
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11508
• DOI: 10.1073/pnas.2420091122
• 发表日期: 2025-03-07
• 关键词: dna demethylation; rod; nrl; differentiation; homeostasis; onecut1; vision; fates

摘要

The retina is responsible for converting light into electrical signals that, when transmitted to the brain, create the sensation of vision. The mammalian retina is epigenetically unique since the differentiation of retinal progenitor cells (RPCs) into retinal cells is accompanied by a decrease in DNA methylation in the promoters of many genes important for retinal development and function. However, the pathway responsible for DNA demethylation and its role in retinal development and function were unknown. We hypothesized that the Ten- Eleven Translocation (TET) family of dioxygenases plays a key role in this pathway. To this end, we knocked out the TET family in RPCs and characterized the TET- deficient and control retinas using various approaches including elecWe found that while the TET- dependent DNA demethylation pathway contributes to the development of many retinal cell types, it is the most significant contributor to rod and cone photoreceptor development and function. We found that genetic ablation of TET enzymes in RPCs prevents demethylation and the activity of genes essential for rod specification and for rod and cone maturation. Reduced activity of genes responsible Meanwhile, reduced activity of genes responsible for rod and cone maturation leads to leading to retinal dystrophy.