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

TET依赖性DNA去甲基化途径在光感受器发育和病理学中的作用

基本信息

批准号：
10709133
负责人：
Dmitry V Ivanov
金额：
$ 37.71万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709133
关键词：
Ablation Animal Model Applications Grants Binding Biochemical Blindness Cell Differentiation process Cessation of life Code Complex Cone DNA DNA Binding Domain DNA Methylation Data Development Dioxygenases Disease Enzymes Epigenetic Process Experimental Designs Eye Development Family Gene Activation Gene Expression Gene Silencing Genes Genetic Genomic DNA Genomic Segment Human Hypermethylation Inherited Laboratories Lead Methylation Modeling Molecular Mus Mutation Natural regeneration Pathogenesis Pathologic Pathology Pathway interactions Phenotype Photoreceptors Process Promoter Regions Protein Family Protein translocation Publishing Retina Retinal Cone Retinal Degeneration Retinitis Pigmentosa Rod Role Signal Transduction Specific qualifier value Study Section Testing Therapeutic USH2A gene Vertebrate Photoreceptors Vision Zebrafish demethylation fetal genome-wide inhibitor neurogenesis postnatal prevent progenitor promoter retinal progenitor cell retinal rods transcription factor

项目摘要

Project Summary Retinitis pigmentosa (RP) and related inherited photoreceptor dystrophies are characterized by progressive photoreceptor loss, resulting in poor vision or even blindness. While these disorders are caused by the mutations of various genes, mutations in RHO, USH2A, PRPH2, RP1, CNGB1, EYS, PDE6A, PDE6G, PDE6C, PDE6H, GNAT1, and NR2E3 account for a substantial number of cases. We recently performed a genome-wide DNA methylation analysis of human and murine fetal retinas (which mostly contain retinal progenitor cells [RPCs]), postnatal murine RPCs, and mature photoreceptors. We discovered that the promoters of all of the genes above were highly methylated (hypermethylated) in DNA isolated from fetal retinas and RPCs. The methylation of these promoters was significantly reduced during RPC differentiation into photoreceptors and accompanied by an increased expression of the corresponding genes. It is generally accepted that DNA methylation in promoter regions silences gene expression, while DNA demethylation should occur to allow gene expression. Unsuccessful demethylation of the promoters of the genes above during RPC differentiation into photoreceptors may reduce or even eliminate their activity, leading to photoreceptor dystrophies without any mutations in the genomic DNA. Thus, not only mutations in DNA but also retina- specific epigenetic changes in the DNA may contribute to the pathogenesis of RP and related diseases, indicating the importance of understanding the DNA demethylation pathway during photoreceptor development. The ten–eleven translocation (TET) protein family has a vital role in DNA demethylation and regulates eye development and neurogenesis in various species. Our data and the results of other laboratories indicate that the TET-dependent DNA demethylation pathway controls photoreceptor development. The objectives of this project are to gain a detailed understanding of how the TET-driven DNA demethylation pathway specifies the differentiation of RPCs into photoreceptors, and to investigate how irregularities in its activity lead to photoreceptor death and retinal degeneration. Using a rigorous experimental design, we will explore this pathway in accordance to our specific aims: 1) determine whether the TET-dependent DNA demethylation pathway acts as a “vertical” epigenetic “switch” between progenitor and photoreceptor precursor fates in the developing retina; 2) determine whether the TET-dependent DNA demethylation pathway functions as a “horizontal” epigenetic “switch” between rod and cone photoreceptor phenotypes; 3) determine whether TET enzymes require transcription factors with DNA binding domains acting as TET binding partners to specify target genes for demethylation and activation during photoreceptor development. To reach these objectives, we will employ animal models and a wide range of biochemical, molecular, and epigenetic approaches, striving to obtain robust and unbiased results. Upon the completion of the project, we expect the results to reveal the role of epigenetic mechanisms in photoreceptor normal and pathological development.

项目总结