TY - JOUR
T1 - Epirubicin Alters DNA Methylation Profiles Related to Cardiotoxicity
AU - Nguyen, N.
AU - Lienhard, M.
AU - Herwig, R.
AU - Kleinjans, J.
AU - Jennen, D.
N1 - Funding Information:
This research was funded by the 7th Framework Program of the European Union (FP7/2007-2013), grant number 602156 for the HeCaToS project.
Publisher Copyright:
Copyright: © 2022 The Author(s)
PY - 2022/6/1
Y1 - 2022/6/1
N2 - 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).
AB - 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).
KW - DNA methylation
KW - epirubicin
KW - MeDIP-seq
KW - toxicogenomics
KW - side effect
KW - READ ALIGNMENT
KW - HEART
U2 - 10.31083/j.fbl2706173
DO - 10.31083/j.fbl2706173
M3 - Article
C2 - 35748249
SN - 2768-6701
VL - 27
JO - Frontiers in Bioscience (Landmark Edition)
JF - Frontiers in Bioscience (Landmark Edition)
IS - 6
M1 - 173
ER -