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Chinese Science Bulletin, Volume 65 , Issue 5 : 392-400(2020) https://doi.org/10.1360/TB-2019-0437

Identification and prediction of molecular targets related to space radiation protection based on associated networks

Dafei Xie 1, Hua Guan 1, Chan Fan 2, Sai Hu 3, Xiaodan Liu 1, Yi Xie 4, Yu Wang 1, Hong Zhang 4,*, Pingkun Zhou 1,*
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  • ReceivedSep 26, 2019
  • AcceptedOct 17, 2019
  • PublishedDec 27, 2019
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Abstract

The effect of cosmic radiation on astronauts is a major barrier for human space exploration. In particular, medical protection against heavy ion radiation-induced injury is one of the key approaches in counteracting cosmic radiation to humans. In recent years, with the rapid accumulation of high-throughput data including gene expression profiles and omics-based data such as protein-protein interactions (PPI), large-scaled network pharmacology analyses can now be conducted. Exploring human genes with potentially high correlation to protection against radiation is becoming an important component and a new approach in heavy ion radiation study owing to advances in rational computational methods based on systems biology techniques.

In this study, heavy ion accelerators were employed to simulate cosmic radiation and a pipeline was constructed to identify activated subnetworks of significantly differentially expressed genes and to predict essential genes related to radiation-induced injury protection. Human lymphoblastoid AHH-1 cells were irradiated with 0.5 or 2 Gy of carbon ions (12C6+). Two kinds of existing radioprotective agents 523 and VND3207 were separately used in vitro 0.5 h before irradiation. Gene expression profiles of the cells were obtained by microarray 4 h after irradiation without and with the treatment of radioprotective agents. The networks of gene expression regulation were constructed based on PPI integrated from Human Protein Reference Database (HPRD). Simulated annealing algorithm was then used to extract activated subnetworks and potential candidate molecular targets including PPM1A, RIF1, CASP3, TFE3 and RIN1 were proposed according to their degrees of connection. Further gene set enrichment analysis (GSEA) indicated significantly enriched clusters of the identified genes in molecular functions including transcription regulator activity, transcription activator activity, enzyme activator activity, protein kinase activity and zinc ion binding. The most enriched clusters in cell components included nuclear body, transcription factor complex, cell junction, chromosome and cytoplasmic side of membrane. The most enriched biological processes were regulation of RNA metabolism, intracellular signal transduction, regulation of neuron death, regulation of cellular component and phosphorylation. We further investigated the expression of RIF1 before and after irradiation with 0.5 and 2 Gy of 12C6+ in Hela cells by western blotting. Expression of RIF1 increased significantly after irradiation and the relative expression in cells 4h after irradiation was greater than 2-fold that of the control. This study took gene correlation into consideration in addition to their differential expression. It provides promising candidates for further discovery of anti-radiation drugs and will be of importance in promoting cosmic radiation protection techniques in long-term manned space programs and deep space exploration missions. In addition, considerable support and clues may also be revealed from the data generated in this study for future research on the underlying mechanisms in radiation-induced injury and medical protection against cosmic radiation.


Funded by

国家自然科学基金(11705283)

中国科学技术协会“青年人才托举工程”项目(CSTQT2017003)

全军医学科技青年培育计划孵化项目(17QNP037)

军事医学科学院军事医学创新基金(2017CXJJ18)


Supplement

补充材料

图S1 不同剂量碳离子(12C6+)辐照和防护药物作用下显著差异表达基因激活子网

图S2 不同剂量碳离子(12C6+)辐照和防护药物干预相关基因表达量调节网络

表S1 不同剂量碳离子(12C6+)辐照和防护药物干预后映射到人类蛋白质相互作用网络上的基因表达量及变化情况

表S2 不同剂量碳离子(12C6+)辐照和防护药物作用下显著差异表达基因激活子网节点属性

本文以上补充材料见网络版csb.scichina.com. 补充材料为作者提供的原始数据, 作者对其学术质量和内容负责.


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  • Click to view Download high-quality image

    Figure 1

    Identifying activated subnetworks of significantly differentially expressed genes (b) from the network of gene expression regulation of cells treated with 0.5 Gy of carbon ions (12C6+) and 523 (a). Red nodes correspond to up-regulated genes while green ones correspond to down-regulated genes. Size of the nodes is proportional to their fold changes. Nodes with fold changes greater than 2 were marked

  • Click to view Download high-quality image

    Figure 2

    Enriched clusters of potential essential molecular targets related to radiation protection

  • Click to view Download high-quality image

    Figure 3

    Effects of carbon ions (12C6+) on expression of RIF1. Results presented are the means ± SD of each group. *P<0.05 relative to control and **P<0.01 relative to control. (a) The case of cells irradiated by 0.5 Gy of 12C6+; (b) the case in 2 Gy of 12C6+

  • Table 1   Potential essential molecular targets of cells treated with of carbon ions (C) and 523

    基因

    药物干预后调节方向

    药物干预后调节倍数

    辐照后调节方向

    辐照后调节倍数

    PPM1A

    上调

    2.475

    下调

    1.861

    TSC22D1

    上调

    2.449

    下调

    4.842

    RIF1

    上调

    2.406

    下调

    1.629

    GMEB1

    上调

    2.369

    下调

    1.891

    PDCD6IP

    上调

    2.355

    下调

    1.414

    PRKAA1

    上调

    2.329

    下调

    2.199

    GDI1

    上调

    2.195

    下调

    2.705

    JAK1

    上调

    2.185

    下调

    2.447

    CUL5

    上调

    2.045

    下调

    1.420

    CREB1

    上调

    2.036

    下调

    2.416

    ATXN2L

    上调

    2.032

    下调

    2.627

  • Table 2   Potential essential molecular targets of cells treated with different doses of carbon ions (C) and radioprotective agents

    基因

    辐射剂量(Gy)

    干预药物

    药物干预后调节方向

    药物干预后调节倍数

    辐照后

    调节方向

    辐照后调节倍数

    CASP3

    0.5

    VND3207

    下调

    2.475

    上调

    1.010

    IFI16

    0.5

    VND3207

    下调

    2.369

    上调

    1.059

    PSMD11

    0.5

    VND3207

    下调

    2.195

    上调

    1.055

    SMN1

    0.5

    VND3207

    上调

    2.045

    下调

    1.672

    TFE3

    2.0

    523

    上调

    3.064

    下调

    1.455

    GTF2A1

    2.0

    523

    下调

    3.002

    上调

    1.695

    PPM1A

    2.0

    523

    下调

    2.469

    上调

    1.342

    BDP1

    2.0

    523

    下调

    2.414

    上调

    1.485

    KRT18

    2.0

    523

    下调

    2.335

    上调

    2.426

    RIN1

    2.0

    VND3207

    下调

    3.255

    上调

    1.143

    ATRX

    2.0

    VND3207

    下调

    2.934

    上调

    1.818

    C1orf103

    2.0

    VND3207

    下调

    2.549

    上调

    1.591

    SMN1

    2.0

    VND3207

    下调

    2.361

    上调

    1.138

    RAPSN

    2.0

    VND3207

    下调

    2.143

    上调

    1.405

    SMAD7

    2.0

    VND3207

    下调

    2.054

    上调

    1.314

    PFN1

    2.0

    VND3207

    上调

    2.049

    下调

    1.077