Cardiac radiotherapy–induced epigenetic memory underlies electrophysiologic and metabolic reprogramming
Samuel D. Jordan, Shuhua Fu, Abigail Fulkerson, Donghua Hu, Sherwin Ng, David M. Zhang, Sneha Manikandan, Jeffrey Szymanski, Nan Hu, Yuqian Xie, Anish Bedi, James Tabor, Lauren Boggs-Bailey, Lori Strong, Stephanie Hicks, Lavanya Aryan, Nishanth Gabriel, Geoffrey D. Hugo, Kuo-Chan Weng, Nathaniel Huebsch, Julie K. Schwarz, Bo Zhang, Stacey L. Rentschler
Samuel D. Jordan, Shuhua Fu, Abigail Fulkerson, Donghua Hu, Sherwin Ng, David M. Zhang, Sneha Manikandan, Jeffrey Szymanski, Nan Hu, Yuqian Xie, Anish Bedi, James Tabor, Lauren Boggs-Bailey, Lori Strong, Stephanie Hicks, Lavanya Aryan, Nishanth Gabriel, Geoffrey D. Hugo, Kuo-Chan Weng, Nathaniel Huebsch, Julie K. Schwarz, Bo Zhang, Stacey L. Rentschler
View: Text | PDF
Research Article Cardiology Cell biology

Cardiac radiotherapy–induced epigenetic memory underlies electrophysiologic and metabolic reprogramming

Abstract

Stereotactic arrhythmia radiotherapy (STAR) is emerging as a highly effective treatment for ventricular tachycardia (VT). Growing evidence indicates that STAR favorably reprograms the electrical substrate by speeding conduction and/or prolonging repolarization via modulation of ion channel expression, although the mechanisms by which single-fraction radiation mediates durable changes in gene expression are incompletely understood. Here, we identify dynamic changes in the cardiomyocyte epigenome and transcriptome after irradiation (IR) in vivo and in vitro, including durably increased expression and chromatin accessibility of Scn5a (encodes the α subunit of the sodium channel, NaV1.5), demonstrating a role for epigenetic memory in conduction velocity (CV) increases observed after STAR. Transcriptomic and epigenetic sequencing further identified dynamic changes in gene expression and regulatory regions involved in cellular repolarization, calcium handling, and metabolism after IR. These changes were mirrored by dose-dependent and cell-autonomous changes in repolarization, calcium flux, and mitochondrial respiration, highlighting important cellular processes that may mediate the therapeutic effects of STAR. Overall, we found that cardiomyocytes exposed to a single fraction of high-dose IR exhibited epigenetic reprogramming that mediated broad and dynamic physiologic responses.

Authors

Samuel D. Jordan, Shuhua Fu, Abigail Fulkerson, Donghua Hu, Sherwin Ng, David M. Zhang, Sneha Manikandan, Jeffrey Szymanski, Nan Hu, Yuqian Xie, Anish Bedi, James Tabor, Lauren Boggs-Bailey, Lori Strong, Stephanie Hicks, Lavanya Aryan, Nishanth Gabriel, Geoffrey D. Hugo, Kuo-Chan Weng, Nathaniel Huebsch, Julie K. Schwarz, Bo Zhang, Stacey L. Rentschler

×

Figure 4

25 Gy IR alters the epigenetic landscape of hiPSC-CMs.

Options: View larger image (or click on image) Download as PowerPoint
25 Gy IR alters the epigenetic landscape of hiPSC-CMs. (A) PCA of RNA-se...
(A) PCA of RNA-seq samples for sham-treated and day-1, -7, and -14 post-IR time points in iCells. (B) Heatmap of DEGs in iCells over time after 25 Gy IR, organized by k-means clustering with GO term enrichment by cluster. (C) Volcano plots for genomic regions with increased (red) and decreased (blue) reads from CUT&Tag experiments targeting H3K4me3, H3K4me1, and H3K27ac, with GO term enrichment. (D) ATAC-seq and H3K27ac Matplots and heatmaps in sham-treated (dark blue), day-7 IR-treated (light blue), and day-14 IR-treated (light green) hiPSC-CMs for increased and decreased differentially acetylated regions. (E) HOMER Motif analysis of TF binding motifs enriched in DMRs. (F) Genome browser plot of the SCN5A locus showing changes in the epigenetic landscape after 25 Gy IR. (G) Heatmap of RNA expression for genes in the GO term “Membrane depolarization during action potential.” (H) mRNA CN5A transcript levels from RNA-seq (P values were determined by Wilcoxon ranked-sum test).