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
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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

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Figure 6

IR transcriptionally regulates mitochondrial physiology and OXPHOS.

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IR transcriptionally regulates mitochondrial physiology and OXPHOS. (A a...
(A and B) Heatmaps for transcript levels of genes in mitochondrial respiratory chain complex I and IV for iCells (A) and WTC hiPSC-CMs (B) over time after 25 Gy IR. RPKM, reads per kilobase per million mapped reads. (C and D) OCR in iCells 48 hours after varying IR doses (C) or over time after 25 Gy (D) (n ≥10 replicates from 1 cryovial; OCR, oxygen consumption rate). (E) Percentage of cells positive for CellROS by flow cytometry 48 hours after 25 Gy in iCells (n = 3 replicates; 1-way ANOVA: P < 0.0001; Tukey’s post hoc test: ***Padj,sham–15Gy = 0.0002, ****Padj,sham–25Gy < 0.0001). (F) Percentage of cells positive for MitoSOX by flow cytometry 1 and 7 days after 25 Gy in iCells (n = 3 replicates; unpaired t tests: day 1 *P = 0.008, day 7 *P = 0.008). (G and H) PCA plots from Myh6-SOD versus WT mice after sham treatment, 2 days after IR, and 6 weeks after IR for male (G) and female (H) mice. (I and J) Euler plots showing overlap of DEGs across time points in Myh6-SOD mice after 25 Gy in male (I) and female (J) mice. Up, higher expression in WT mice; dn, lower expression in WT mice.