Cargando…
Targeted DNA Demethylation: Vectors, Effectors and Perspectives
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 t...
Autores principales: | , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215725/ https://www.ncbi.nlm.nih.gov/pubmed/37239005 http://dx.doi.org/10.3390/biomedicines11051334 |
_version_ | 1785048132289036288 |
---|---|
author | Yano, Naohiro Fedulov, Alexey V. |
author_facet | Yano, Naohiro Fedulov, Alexey V. |
author_sort | Yano, Naohiro |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10215725 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102157252023-05-27 Targeted DNA Demethylation: Vectors, Effectors and Perspectives Yano, Naohiro Fedulov, Alexey V. Biomedicines Review 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. MDPI 2023-04-30 /pmc/articles/PMC10215725/ /pubmed/37239005 http://dx.doi.org/10.3390/biomedicines11051334 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Yano, Naohiro Fedulov, Alexey V. Targeted DNA Demethylation: Vectors, Effectors and Perspectives |
title | Targeted DNA Demethylation: Vectors, Effectors and Perspectives |
title_full | Targeted DNA Demethylation: Vectors, Effectors and Perspectives |
title_fullStr | Targeted DNA Demethylation: Vectors, Effectors and Perspectives |
title_full_unstemmed | Targeted DNA Demethylation: Vectors, Effectors and Perspectives |
title_short | Targeted DNA Demethylation: Vectors, Effectors and Perspectives |
title_sort | targeted dna demethylation: vectors, effectors and perspectives |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215725/ https://www.ncbi.nlm.nih.gov/pubmed/37239005 http://dx.doi.org/10.3390/biomedicines11051334 |
work_keys_str_mv | AT yanonaohiro targeteddnademethylationvectorseffectorsandperspectives AT fedulovalexeyv targeteddnademethylationvectorseffectorsandperspectives |