Transcriptional regulatory network response of A549 cells to heavy ion irradiation

The therapeutic effects of radiotherapy can be affected by cancer cells responding adaptively. The physical and biological characteristics of heavy ion beams make them ideal for use in radiotherapy. Cancer response to heavy ion therapy, however, remains unclear. Using ATAC-seq and RNA-seq analysis of A549 cells treated with heavy ions and IOX1 inhibitors, we determined the chromatin accessibility landscape of non-small cell lung cancer (NSCLC) cell line A549 after treatment.Alterations in chromatin accessibility caused by heavy ion treatments were occurred most often in promoter, intron and 5UTR regions of differentially expressed genes. We further identified CTCF as a key transcription factor in response to heavy ion therapy. The target genes regulated by CTCF were involved in the cell cycle and DNA damage repair pathway. Meanwhile, the chromatin accessibility changes induced by heavy ions were clearly different from those induced by chemosensitizer. And the difference in chromatin accessibility between LET30 and LET50 heavy ion was mostly different in degree, indicating a LETdependent effect of heavy ions on the regulation of gene transcription by changing chromatin accessibility. A valuable contribution to understanding gene regulatory networks and the biological effects of heavy ion therapy is provided by our study.

放疗的治疗效果可受癌细胞适应性应答的影响。重离子束具备优异的物理与生物学特性，是放疗的理想手段。然而，癌细胞对重离子治疗的应答机制仍未明确。本研究通过对经重离子及IOX1抑制剂处理的A549细胞开展转座酶可及性测序（ATAC-seq）与RNA测序（RNA-seq）分析，解析了非小细胞肺癌（NSCLC）细胞系A549经处理后的染色质可及性全景图谱。重离子处理诱导的染色质可及性改变，多富集于差异表达基因的启动子、内含子及5'非翻译区（5UTR）区域。本研究进一步确认CCCTC结合因子（CTCF）是重离子治疗应答过程中的关键转录因子，其调控的靶基因参与细胞周期与DNA损伤修复通路。与此同时，重离子诱导的染色质可及性改变与化学增敏剂诱导的改变存在显著差异。LET30与LET50重离子之间的染色质可及性差异主要体现为程度上的不同，这表明重离子可通过改变染色质可及性调控基因转录，且该效应具有线性能量转移（LET）依赖性。本研究为解析基因调控网络及重离子治疗的生物学效应提供了极具价值的理论参考与实验依据。