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Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes
The potential mechanism of myelodysplastic syndromes (MDS) progressing to acute myeloid leukemia (AML) remains poorly elucidated. It has been proved that epigenetic alterations play crucial roles in the pathogenesis of cancer progression including MDS. However, fewer studies explored the whole-genom...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679421/ https://www.ncbi.nlm.nih.gov/pubmed/33219204 http://dx.doi.org/10.1038/s41419-020-03213-2 |
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author | Zhou, Jing-dong Zhang, Ting-juan Xu, Zi-jun Deng, Zhao-qun Gu, Yu Ma, Ji-chun Wen, Xiang-mei Leng, Jia-yan Lin, Jiang Chen, Su-ning Qian, Jun |
author_facet | Zhou, Jing-dong Zhang, Ting-juan Xu, Zi-jun Deng, Zhao-qun Gu, Yu Ma, Ji-chun Wen, Xiang-mei Leng, Jia-yan Lin, Jiang Chen, Su-ning Qian, Jun |
author_sort | Zhou, Jing-dong |
collection | PubMed |
description | The potential mechanism of myelodysplastic syndromes (MDS) progressing to acute myeloid leukemia (AML) remains poorly elucidated. It has been proved that epigenetic alterations play crucial roles in the pathogenesis of cancer progression including MDS. However, fewer studies explored the whole-genome methylation alterations during MDS progression. Reduced representation bisulfite sequencing was conducted in four paired MDS/secondary AML (MDS/sAML) patients and intended to explore the underlying methylation-associated epigenetic drivers in MDS progression. In four paired MDS/sAML patients, cases at sAML stage exhibited significantly increased methylation level as compared with the matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involving in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were involved in MDS progression. Targeted bisulfite sequencing further identified that aberrant GFRA1, IRX1, NPY, and ZNF300 methylation were frequent events in an additional group of de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Subsequently, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was confirmed by real-time quantitative methylation-specific PCR. It was illustrated that ZNF300 methylation could act as a potential biomarker for the diagnosis and prognosis in MDS and AML patients. Functional experiments demonstrated the anti-proliferative and pro-apoptotic role of ZNF300 overexpression in MDS-derived AML cell-line SKM-1. Collectively, genome-wide DNA hypermethylation were frequent events during MDS progression. Among these changes, ZNF300 methylation, a regulator of ZNF300 expression, acted as an epigenetic driver in MDS progression. These findings provided a theoretical basis for the usage of demethylation drugs in MDS patients against disease progression. |
format | Online Article Text |
id | pubmed-7679421 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-76794212020-11-24 Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes Zhou, Jing-dong Zhang, Ting-juan Xu, Zi-jun Deng, Zhao-qun Gu, Yu Ma, Ji-chun Wen, Xiang-mei Leng, Jia-yan Lin, Jiang Chen, Su-ning Qian, Jun Cell Death Dis Article The potential mechanism of myelodysplastic syndromes (MDS) progressing to acute myeloid leukemia (AML) remains poorly elucidated. It has been proved that epigenetic alterations play crucial roles in the pathogenesis of cancer progression including MDS. However, fewer studies explored the whole-genome methylation alterations during MDS progression. Reduced representation bisulfite sequencing was conducted in four paired MDS/secondary AML (MDS/sAML) patients and intended to explore the underlying methylation-associated epigenetic drivers in MDS progression. In four paired MDS/sAML patients, cases at sAML stage exhibited significantly increased methylation level as compared with the matched MDS stage. A total of 1090 differentially methylated fragments (DMFs) (441 hypermethylated and 649 hypomethylated) were identified involving in MDS pathogenesis, whereas 103 DMFs (96 hypermethylated and 7 hypomethylated) were involved in MDS progression. Targeted bisulfite sequencing further identified that aberrant GFRA1, IRX1, NPY, and ZNF300 methylation were frequent events in an additional group of de novo MDS and AML patients, of which only ZNF300 methylation was associated with ZNF300 expression. Subsequently, ZNF300 hypermethylation in larger cohorts of de novo MDS and AML patients was confirmed by real-time quantitative methylation-specific PCR. It was illustrated that ZNF300 methylation could act as a potential biomarker for the diagnosis and prognosis in MDS and AML patients. Functional experiments demonstrated the anti-proliferative and pro-apoptotic role of ZNF300 overexpression in MDS-derived AML cell-line SKM-1. Collectively, genome-wide DNA hypermethylation were frequent events during MDS progression. Among these changes, ZNF300 methylation, a regulator of ZNF300 expression, acted as an epigenetic driver in MDS progression. These findings provided a theoretical basis for the usage of demethylation drugs in MDS patients against disease progression. Nature Publishing Group UK 2020-11-20 /pmc/articles/PMC7679421/ /pubmed/33219204 http://dx.doi.org/10.1038/s41419-020-03213-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Zhou, Jing-dong Zhang, Ting-juan Xu, Zi-jun Deng, Zhao-qun Gu, Yu Ma, Ji-chun Wen, Xiang-mei Leng, Jia-yan Lin, Jiang Chen, Su-ning Qian, Jun Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes |
title | Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes |
title_full | Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes |
title_fullStr | Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes |
title_full_unstemmed | Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes |
title_short | Genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes |
title_sort | genome-wide methylation sequencing identifies progression-related epigenetic drivers in myelodysplastic syndromes |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679421/ https://www.ncbi.nlm.nih.gov/pubmed/33219204 http://dx.doi.org/10.1038/s41419-020-03213-2 |
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