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 2

Cardiac radiation induces dynamic changes in gene expression and chromatin accessibility in murine PCM1+ nuclei.

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Cardiac radiation induces dynamic changes in gene expression and chromat...
(A) PCA for sham (green) and 42 days after IR (blue) mouse PCM1+ nuclei transcriptomes. (B) Volcano plot of significantly upregulated (green) and downregulated (blue) transcripts in day-42 post-IR–treated versus sham-treated murine cardiomyocyte nuclei. (C) Selected GO terms enriched in upregulated (green) and downregulated (blue) genes. (D) PCA of ATAC-seq samples for PCM1+ nuclei from sham-treated, day-2 (D2) post-IR, and day-42 (D42) post-IR mouse hearts. (E) Heatmap of DARs in PCM1+ nuclei over time after 25 Gy compared with sham, organized by k-means clustering. (F) Selected GO term analysis for k-means clustered DARs for clusters 1–3. (G) HOMER motif analysis of TF binding motifs enriched in each cluster of DARs. (H) mRNA transcript levels of selected TFs identified in motif enrichment analysis (H) and Scn5a (I) in sham-treated nuclei versus day-42 post-IR PCM1+ nuclei (P values were determined by Wilcoxon ranked-sum test). (J) Genome browser plot of the Scn5a gene showing sham and day-42 post-IR ATAC-seq tracings, as well as ChIP-seq chromatin occupancy for Tbx20 (orange), Tbx5 (red), GATA4 (purple), and Stat3 (green). Significant DARs are highlighted below the ATAC-seq Matplots. Insets highlight the TSS (left) and known enhancer elements (left).