表阿霉素改变与心脏毒性相关的 DNA 甲基化谱。

Epirubicin Alters DNA Methylation Profiles Related to Cardiotoxicity.

机构信息

Department of Toxicogenomics, GROW School for Oncology and Reproduction, Maastricht University, 6229ER Maastricht, The Netherlands.

Department of Computational Molecular Biology, Max-Planck-Institute for Molecular Genetics, 14195 Berlin, Germany.

出版信息

Front Biosci (Landmark Ed). 2022 Jun 1;27(6):173. doi: 10.31083/j.fbl2706173.

DOI:10.31083/j.fbl2706173

PMID:35748249

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 , , , , , , and , 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).

摘要

背景

表阿霉素（EPI）是一种重要的抗癌药物，其心脏毒性副作用众所周知。研究表观遗传修饰，如 DNA 甲基化，可以帮助我们了解心脏组织中与 EPI 相关的毒性机制。在这项研究中，我们分析了相关的人类细胞模型中的 DNA 甲基化谱，并在转录组水平上检查了差异甲基化基因的表达，以了解 DNA 甲基化的变化如何影响与 EPI 诱导的心脏毒性相关的基因表达。

方法

人类心脏微组织在 2 周内暴露于治疗剂量或毒性（IC20）EPI 剂量下。在暴露 2、8、24、72、168、240 和 336 小时后，从微组织中重复收集 3 份 DNA 和 RNA。使用甲基化 DNA 免疫沉淀测序（MeDIP-seq）分析检测 EPI 处理和对照样品中的 DNA 甲基化水平。使用最近发表的工作流程，使用 QSEA 包分析和处理 MeDIP-seq 数据。在相同的样品中使用 RNA 测序（RNA-seq）测量全基因表达。

结果

在处理 MeDIP-seq 数据后，我们在所有 EPI 处理、EPI 治疗和 EPI 毒性剂量处理与对照相比的样本中检测到 35、37 和 15 个候选基因，分别显示出强烈的甲基化改变。对于一些基因，基因表达的变化反映了 DNA 甲基化的调节。

结论

观察到的 DNA 甲基化修饰为 EPI 诱导的心脏毒性提供了进一步的见解。在 EPI 处理下，多个差异甲基化基因，如、、、、、、和，已被涉及不同的心脏功能障碍机制。与其他差异甲基化基因一起，这些基因可以作为进一步研究 EPI 相关毒性机制的候选基因。

数据存储库

数据是由 HeCaToS 项目（http://www.ebi.ac.uk/biostudies）在 S-HECA433 和 S-HECA434 号下为 MeDIP-seq 数据和 S-HECA11 号下为 RNA-seq 数据生成的。R 代码可在 Github（https://github.com/NhanNguyen000/MeDIP）上获得。