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Prolonged Treatment with DNMT Inhibitors Induces Distinct Effects in Promoters and Gene-Bodies

Treatment with the demethylating drugs 5-azacytidine (AZA) and decitabine (DAC) is now recognised as an effective therapy for patients with Myelodysplastic Syndromes (MDS), a range of disorders arising in clones of hematopoietic progenitor cells. A variety of cell models have been used to study the...

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Autores principales: Wong, Yan-Fung, Jakt, Lars Martin, Nishikawa, Shin-Ichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735498/
https://www.ncbi.nlm.nih.gov/pubmed/23940695
http://dx.doi.org/10.1371/journal.pone.0071099
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author Wong, Yan-Fung
Jakt, Lars Martin
Nishikawa, Shin-Ichi
author_facet Wong, Yan-Fung
Jakt, Lars Martin
Nishikawa, Shin-Ichi
author_sort Wong, Yan-Fung
collection PubMed
description Treatment with the demethylating drugs 5-azacytidine (AZA) and decitabine (DAC) is now recognised as an effective therapy for patients with Myelodysplastic Syndromes (MDS), a range of disorders arising in clones of hematopoietic progenitor cells. A variety of cell models have been used to study the effect of these drugs on the methylation of promoter regions of tumour suppressor genes, with recent efforts focusing on the ability of these drugs to inhibit DNA methylation at low doses. However, it is still not clear how nano-molar drug treatment exerts its effects on the methylome. In this study, we have characterised changes in DNA methylation caused by prolonged low-dose treatment in a leukemic cell model (SKM-1), and present a genome-wide analysis of the effects of AZA and DAC. At nano-molar dosages, a one-month continuous treatment halved the total number of hypermethylated probes in leukemic cells and our analysis identified 803 candidate regions with significant demethylation after treatment. Demethylated regions were enriched in promoter sequences whereas gene-body CGIs were more resistant to the demethylation process. CGI methylation in promoters was strongly correlated with gene expression but this correlation was lost after treatment. Our results indicate that CGI demethylation occurs preferentially at promoters, but that it is not generally sufficient to modify expression patterns, and emphasises the roles of other means of maintaining cell state.
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spelling pubmed-37354982013-08-12 Prolonged Treatment with DNMT Inhibitors Induces Distinct Effects in Promoters and Gene-Bodies Wong, Yan-Fung Jakt, Lars Martin Nishikawa, Shin-Ichi PLoS One Research Article Treatment with the demethylating drugs 5-azacytidine (AZA) and decitabine (DAC) is now recognised as an effective therapy for patients with Myelodysplastic Syndromes (MDS), a range of disorders arising in clones of hematopoietic progenitor cells. A variety of cell models have been used to study the effect of these drugs on the methylation of promoter regions of tumour suppressor genes, with recent efforts focusing on the ability of these drugs to inhibit DNA methylation at low doses. However, it is still not clear how nano-molar drug treatment exerts its effects on the methylome. In this study, we have characterised changes in DNA methylation caused by prolonged low-dose treatment in a leukemic cell model (SKM-1), and present a genome-wide analysis of the effects of AZA and DAC. At nano-molar dosages, a one-month continuous treatment halved the total number of hypermethylated probes in leukemic cells and our analysis identified 803 candidate regions with significant demethylation after treatment. Demethylated regions were enriched in promoter sequences whereas gene-body CGIs were more resistant to the demethylation process. CGI methylation in promoters was strongly correlated with gene expression but this correlation was lost after treatment. Our results indicate that CGI demethylation occurs preferentially at promoters, but that it is not generally sufficient to modify expression patterns, and emphasises the roles of other means of maintaining cell state. Public Library of Science 2013-08-06 /pmc/articles/PMC3735498/ /pubmed/23940695 http://dx.doi.org/10.1371/journal.pone.0071099 Text en © 2013 WONG et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Wong, Yan-Fung
Jakt, Lars Martin
Nishikawa, Shin-Ichi
Prolonged Treatment with DNMT Inhibitors Induces Distinct Effects in Promoters and Gene-Bodies
title Prolonged Treatment with DNMT Inhibitors Induces Distinct Effects in Promoters and Gene-Bodies
title_full Prolonged Treatment with DNMT Inhibitors Induces Distinct Effects in Promoters and Gene-Bodies
title_fullStr Prolonged Treatment with DNMT Inhibitors Induces Distinct Effects in Promoters and Gene-Bodies
title_full_unstemmed Prolonged Treatment with DNMT Inhibitors Induces Distinct Effects in Promoters and Gene-Bodies
title_short Prolonged Treatment with DNMT Inhibitors Induces Distinct Effects in Promoters and Gene-Bodies
title_sort prolonged treatment with dnmt inhibitors induces distinct effects in promoters and gene-bodies
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3735498/
https://www.ncbi.nlm.nih.gov/pubmed/23940695
http://dx.doi.org/10.1371/journal.pone.0071099
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