辐射诱导的染色质拓扑关联结构域层级变化及其在细胞辐射响应中的作用

基因组三维结构在基因表达调控中发挥重要作用,染色质拓扑关联结构域(topologically associated domain,TAD)是DNA复制和基因转录的基本功能单位,也是DNA损伤修复的功能单元,在辐射诱导的DNA损伤修复中发挥重要作用。近期研究表明,TAD并非是完全独立的结构单元,其内部常呈现多层级结构,对基因表达具有重要调控作用。为探究TAD多层级结构在细胞辐射响应中的作用,本研究使用TAD层级结构识别算法OnTAD对Gene expression omnibus数据库中5Gy X射线照射的淋巴细胞、成纤维细胞和毛细血管扩张性共济失调突变(ataxia telangiectasia mutated,ATM)基因缺陷的成纤维细胞,共26个样本的Hi-C(high-through chromosome conformation capture,Hi-C)数据进行分析,发现辐射后细胞的TAD层级结构出现规律性变化,高层级TAD缺失较多,低层级TAD相对保守;辐射诱导的TAD层级结构变化通过调节基因表达参与细胞辐射响应;ATM是辐射诱导TAD层级结构变化和恢复的重要因子。本研究为从TAD多层级结构角度理解基因组三维结构在细胞辐射响应中的作用提供了新思路。

Radiation-induced Hierarchical Topologically Associated Domain Change and Its Role in Cellular Responses to Radiation

The three-dimensional (3D) genome organization plays an important role in gene regulation. As a basic functional unit of the genome, topologically associated domain (TAD) regulates multiple biological processes such as gene expression and DNA replication and plays a role in radiation-induced DNA damage repair. Recent studies showed that TAD is not a completely independent domain but contains hierarchical internal domains, which could be a new mechanism of gene regulation. To explore the role of hierarchical TAD in cellular responses to radiation, we apply the OnTAD algorithm, an optimized nested TAD caller from Hi-C data, to identify hierarchical TAD in 26 Hi-C data fromGene expression omnibus (GEO) database. These data were from irradiated fibroblasts, lymphoblasts and fibroblasts deficient in the ataxia telangiectasia mutated (ATM) gene with 5 Gy X-ray. We observe that X-ray can regularly affect the hierarchy of TAD in which high-level TAD is prone to change and low-level TAD is more conservative. We propose that radiation-induced TAD hierarchy change can regulate cellular responses to radiation by regulating gene expression, and ATM is a necessary factor for radiation-induced TAD hierarchy change and recovery. This study provides new insights into the role of the 3D genome in radiation-induced cellular responses from the perspective of hierarchical TAD structures.