Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Unveiling the distinctive impact of radiation on cardiac ventricular regions and the right atrium using multi-omics approaches

ABSTRACT: Radiotherapy (RT)-induced cardiac toxicity is widely acknowledged as a major side effect of RT, which encompasses cardiovascular complications. Despite advances in understanding the underlying biological mechanisms, a complete characterisation of the molecular changes induced by RT in the different cardiac regions is still absent. Here, a multi-omics approach was adopted to longitudinally characterise the unique response to radiation in the heart base (including ventricular base and right atrium), or the apex of the heart. The ventricular base showed a cardiomyopathy phenotype, with pronounced molecular perturbations in metabolism and electrical conduction, while changes in tissue structure were predominant in ventricular apex. We then identified a molecular signature showing that base radiation-mediated remodelling leads to a higher incidence of atrial fibrillation. This study represents a comprehensive characterisation of differential spatiotemporal radiation effects in the heart and highlights several biological pathways that are potentially clinically actionable for cardiac radioprotection and monitoring.

INSTRUMENT(S): Illumina HiSeq 4000

ORGANISM(S): Mus musculus

SUBMITTER: Leo Zeef

PROVIDER: E-MTAB-14630 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Accurate and comprehensive de novo transcriptome profiling in heart is a central issue to better understand cardiac physiology and diseases. Although significant progress has been made in genome-wide profiling for quantitative changes in cardiac gene expression, current knowledge offers limited insights to the total complexity in cardiac transcriptome at individual exon level. To develop more robust bioinformatic approaches to analyze high-throughput RNA sequencing (RNA-Seq) data, with the focus on the investigation of transcriptome complexity at individual exon and transcript levels. In addition to overall gene expression analysis, the methods developed in this study were used to analyze RNA-Seq data with respect to individual transcript isoforms, novel spliced exons, novel alternative terminal exons, novel transcript clusters (i.e., novel genes) and long non-coding RNA genes. We applied these approaches to RNA-Seq data obtained from mouse hearts following pressure-overload induced by trans-aortic constriction. Based on experimental validations, analyses of the features of the identified exons/transcripts, and expression analyses including previously published RNA-Seq data, we demonstrate that the methods are highly effective in detecting and quantifying individual exons and transcripts. Novel insights inferred from the examined aspects of the cardiac transcriptome open ways to further experimental investigations. Our work provided a comprehensive set of methods to analyze mouse cardiac transcriptome complexity at individual exon and transcript levels. Applications of the methods may infer important new insights to gene regulation in normal and disease hearts in terms of exon utilization and potential involvement of novel components of cardiac transcriptome. Left ventricular tissues were collected from C57BL/6 mice after 1 week (hypertrophy stage, HY) and 8 weeks post trans-aortic constriction (TAC) procedure (heart failure stage, HF), respectively, and their corresponding Sham controls (Sham-HY, Sham-HF). To conduct RNA-Seq analysis, total RNAs from six TAC and Sham-operated mice at the HY stage and four TAC and corresponding Sham mice at the HF stage were obtained.

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Unveiling the distinctive impact of radiation on cardiac ventricular regions and the right atrium using multi-omics approaches

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