Journal
BIOMEDICINES
Volume 11, Issue 5, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines11051334
Keywords
DNA demethylase; DNA-binding domains; gene targeting; epigenetic therapy; vectors
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Aberrant DNA hypermethylation is observed in various diseases, and therapeutic DNA demethylation has the potential to elucidate the importance of epigenetic alterations and open new avenues for treatment. However, current methods are limited in their ability to target specific epimutations. Gene-specific epigenetic editing, using DNA-binding molecules and demethylases, offers a critical approach for re-activating silenced genes. Challenges, such as the need for transgenesis, need to be addressed. This review explores gene-specific DNA demethylation as an innovative therapeutic strategy.
Aberrant DNA hypermethylation at regulatory cis-elements of particular genes is seen in a plethora of pathological conditions including cardiovascular, neurological, immunological, gastrointestinal and renal diseases, as well as in cancer, diabetes and others. Thus, approaches for experimental and therapeutic DNA demethylation have a great potential to demonstrate mechanistic importance, and even causality of epigenetic alterations, and may open novel avenues to epigenetic cures. However, existing methods based on DNA methyltransferase inhibitors that elicit genome-wide demethylation are not suitable for treatment of diseases with specific epimutations and provide a limited experimental value. Therefore, gene-specific epigenetic editing is a critical approach for epigenetic re-activation of silenced genes. Site-specific demethylation can be achieved by utilizing sequence-dependent DNA-binding molecules such as zinc finger protein array (ZFA), transcription activator-like effector (TALE) and clustered regularly interspaced short palindromic repeat-associated dead Cas9 (CRISPR/dCas9). Synthetic proteins, where these DNA-binding domains are fused with the DNA demethylases such as ten-eleven translocation (Tet) and thymine DNA glycosylase (TDG) enzymes, successfully induced or enhanced transcriptional responsiveness at targeted loci. However, a number of challenges, including the dependence on transgenesis for delivery of the fusion constructs, remain issues to be solved. In this review, we detail current and potential approaches to gene-specific DNA demethylation as a novel epigenetic editing-based therapeutic strategy.
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