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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...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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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. |
format | Online Article Text |
id | pubmed-3735498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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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