Radiation-induced epigenetic alterations after low and high LET irradiations
Radiation-induced epigenetic alterations after low and high LET irradiations
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DOI：
10.1016/j.mrfmmm.2010.12.003
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发表时间：
2011-02-10
影响因子：
2.3
通讯作者：
Baulch, Janet E.
中科院分区：
文献类型：
--
作者：
Aypar, Umut;Morgan, William F.;Baulch, Janet E.
表观遗传学，包括DNA甲基化和microRNA(MiRNA)的表达，可能是理解辐射诱导的基因组不稳定(RIGI)的缺失环节。本研究验证了这样一种假设，即辐射引起表观遗传畸变，最终导致RIGL，而低线性能量转移(LET)照射引起的表观遗传像差不同于高LET照射引起的表观遗传像差。用低LET X射线和高LET铁离子照射GM10115细胞，观察其DNA损伤、细胞存活和染色体不稳定性。检测核因子-kappaB、肺癌肿瘤抑制因子1和钙粘蛋白1基因启动子区域、长分布核素1和Alu重复序列甲基化、CpG和非CpG整体甲基化及miRNA表达水平。受照细胞微核诱导率和细胞杀伤率在受照后即刻增加，但在受照后的延迟时间内染色体稳定。在同一延迟时间，观察到重复序列、全局DNA甲基化和miRNA表达的变化。DNA甲基化分析主要显示低甲基化，但也观察到高甲基化。我们证明，在X射线照射后，miRNA的表达水平可以改变，并且这些miRNA参与染色质重塑和DNA甲基化。尽管铁离子引起了更多的染色体损伤和细胞死亡，但暴露于X射线后，表观遗传学变化的发生率高于铁离子。这种区别在miRNA分析中很明显，在高LET照射后，只有3个涉及两个主要途径的miRNA发生了变化，而在低LET照射后，涉及5个主要途径的6个miRNA发生了变化。这项研究还表明，受辐射的细胞获得了表观遗传学的变化，这表明表观遗传学的异常可能出现在细胞中，而不会引发染色体的不稳定性。(C)2010爱思唯尔B.V.保留所有权利。
Epigenetics, including DNA methylation and microRNA (miRNA) expression, could be the missing link in understanding radiation-induced genomic instability (RIGI). This study tests the hypothesis that irradiation induces epigenetic aberrations, which could eventually lead to RIGL and that the epigenetic aberrations induced by low linear energy transfer (LET) irradiation are different than those induced by high LET irradiations. GM10115 cells were irradiated with low LET X-rays and high LET iron (Fe) ions and evaluated for DNA damage, cell survival and chromosomal instability. The cells were also evaluated for specific locus methylation of nuclear factor-kappa B (NF kappa B), tumor suppressor in lung cancer 1 (TSLC1) and cadherin 1 (CDH1) gene promoter regions, long interspersed nuclear element 1 (LINE-1) and Alu repeat element methylation, CpG and non-CpG global methylation and miRNA expression levels. Irradiated cells showed increased micronucleus induction and cell killing immediately following exposure, but were chromosomally stable at delayed times post-irradiation. At this same delayed time, alterations in repeat element and global DNA methylation and miRNA expression were observed. Analyses of DNA methylation predominantly showed hypomethylation, however hypermethylation was also observed. We demonstrate that miRNA expression levels can be altered after X-ray irradiation and that these miRNA are involved in chromatin remodeling and DNA methylation. A higher incidence of epigenetic changes was observed after exposure to X-rays than Fe ions even though Fe ions elicited more chromosomal damage and cell killing. This distinction is apparent at miRNA analyses at which only three miRNA involved in two major pathways were altered after high LET irradiations while six miRNA involved in five major pathways were altered after low LET irradiations. This study also shows that the irradiated cells acquire epigenetic changes suggesting that epigenetic aberrations may arise in the cell without initiating chromosomal instability. (C) 2010 Elsevier B.V. All rights reserved.