Dose rate dependent reduction in chromatin accessibility at transcriptional start sites long time after exposure to gamma radiation

Ionizing radiation (IR) impact cellular and molecular processes that require chromatin remodelling relevant for cellular integrity. However, the cellular implications of ionizing radiation (IR) delivered per time unit (dose rate) are still debated. This study investigates whether the dose rate is relevant for inflicting changes to the epigenome, represented by chromatin accessibility, or whether it is the total dose that is decisive. CBA/CaOlaHsd mice were whole-body exposed to either chronic low dose rate (2.5 mGy/h for 54 d) or the higher dose rates (10 mGy/h for 14 d and 100 mGy/h for 30 h) of gamma radiation (⁶⁰Co, total dose: 3 Gy). Chromatin accessibility was analysed in liver tissue samples using Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-Seq), both one day after and over three months post-radiation (>100 d). The results show that the dose rate contributes to radiation-induced epigenomic changes in the liver at both sampling timepoints. Interestingly, chronic low dose rate exposure to a high total dose (3 Gy) did not inflict long-term changes to the epigenome. In contrast to the acute high dose rate given to the same total dose, reduced accessibility at transcriptional start sites (TSS) was identified in genes relevant for the DNA damage response and transcriptional activity. Our findings link dose rate to essential biological mechanisms that could be relevant for understanding long-term changes after ionizing radiation exposure. However, future studies are needed to comprehend the biological consequence of these findings.

电离辐射（Ionizing Radiation, IR）会影响依赖染色质重塑的细胞与分子过程，此类过程对维持细胞完整性至关重要。然而，按时间单位递送的电离辐射的剂量率所引发的细胞效应仍存在争议。本研究旨在探讨，剂量率是否是影响表观基因组（以染色质可及性为表征）改变的关键因素，抑或是总剂量起决定性作用。研究人员对CBA/CaOlaHsd小鼠实施全身照射，照射方案分为三组：慢性低剂量率组（2.5 mGy/h，持续54天）、较高剂量率组（10 mGy/h，持续14天）以及100 mGy/h组（持续30小时），照射源为钴-60（⁶⁰Co）γ射线，三组总剂量均为3 Gy。分别在照射后1天及100天以上两个时间点，通过转座酶可及性染色质高通量测序（Assay for Transposase-Accessible Chromatin with high-throughput sequencing, ATAC-Seq）分析肝组织样本的染色质可及性。研究结果显示，在两个采样时间点，剂量率均会诱导肝脏表观基因组发生辐射相关改变。值得注意的是，接受3 Gy高总剂量慢性低剂量率照射的小鼠，其表观基因组并未出现长期改变。与总剂量相同的急性高剂量率照射组相比，该慢性照射组中，与DNA损伤应答及转录活性相关的基因的转录起始位点（Transcriptional Start Sites, TSS）处的染色质可及性显著降低。本研究发现将剂量率与核心生物学机制建立了关联，这或有助于理解电离辐射暴露后的长期生物学效应。不过，仍需开展后续研究以阐明本研究发现的生物学意义。