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  Epirubicin Alters DNA Methylation Profiles Related to Cardiotoxicity

Nguyen, N., Lienhard, M., Herwig, R., Kleinjans, J., & Jennen, D. (2022). Epirubicin Alters DNA Methylation Profiles Related to Cardiotoxicity. Frontiers in Bioscience-Landmark, 27(6): 173. doi:10.31083/j.fbl2706173.

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FrontBiosci_Nguyen et al_2022.pdf (Publisher version), 13MB
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Nguyen, Nhan , Author
Lienhard, Matthias1, Author           
Herwig, Ralf1, Author           
Kleinjans, Jos , Author
Jennen, Danyel , Author
Affiliations:
1Bioinformatics (Ralf Herwig), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385701              

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Free keywords: DNA methylation; epirubicin; MeDIP-seq; Toxicogenomics; side effect
 Abstract: Background: Epirubicin (EPI) is an important anticancer drug that is well-known for its cardiotoxic side effect. Studying epigenetic modification such as DNA methylation can help to understand the EPI-related toxic mechanisms in cardiac tissue. In this study, we analyzed the DNA methylation profile in a relevant human cell model and inspected the expression of differentially methylated genes at the transcriptome level to understand how changes in DNA methylation could affect gene expression in relation to EPI-induced cardiotoxicity. Methods: Human cardiac microtissues were exposed to either therapeutic or toxic (IC20) EPI doses during 2 weeks. The DNA and RNA were collected from microtissues in triplicates at 2, 8, 24, 72, 168, 240, and 336 hours of exposure. Methylated DNA immunoprecipitation-sequencing (MeDIP-seq) analysis was used to detect DNA methylation levels in EPI-treated and control samples. The MeDIP-seq data were analyzed and processed using the QSEA package with a recently published workflow. RNA sequencing (RNA-seq) was used to measure global gene expression in the same samples. Results: After processing the MeDIP-seq data, we detected 35, 37, 15 candidate genes which show strong methylated alterations between all EPI-treated, EPI therapeutic and EPI toxic dose-treated samples compared to control, respectively. For several genes, gene expressions changed compatibly reflecting the DNA methylation regulation. Conclusions: The observed DNA methylation modifications provide further insights into the EPI-induced cardiotoxicity. Multiple differentially methylated genes under EPI treatment, such as SMARCA4, PKN1, RGS12, DPP9, NCOR2, SDHA, POLR2A, and AGPAT3, have been implicated in different cardiac dysfunction mechanisms. Together with other differentially methylated genes, these genes can be candidates for further investigations of EPI-related toxic mechanisms. Data Repository: The data has been generated by the HeCaToS project (http://www.ebi.ac.uk/biostudies) under accession numbers S-HECA433 and S-HECA434 for the MeDIP-seq data and S-HECA11 for the RNA-seq data. The R code is available on Github (https://github.com/NhanNguyen000/MeDIP).

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Language(s): eng - English
 Dates: 2022-04-262022-06-01
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.31083/j.fbl2706173
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Title: Frontiers in Bioscience-Landmark
Source Genre: Journal
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Publ. Info: Singapore : IMR Press
Pages: - Volume / Issue: 27 (6) Sequence Number: 173 Start / End Page: - Identifier: ISSN: 2768-6701 (print) 2768-6698 (online)