Proton irradiation induces persistent and tissue-specific DNA methylation changes in the left ventricle and hippocampus.
Proton irradiation induces persistent and tissue-specific DNA methylation changes in the left ventricle and hippocampus.
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DOI：
10.1186/s12864-016-2581-x
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发表时间：
2016-03-31
期刊：
影响因子：
4.4
通讯作者：
Raber J
中科院分区：
文献类型：
--
作者：
Impey S;Pelz C;Tafessu A;Marzulla T;Turker MS;Raber J
质子辐照在使命期间和之后对宇航员构成潜在危险，有丝分裂后的细胞风险最大，因为它们不能稀释通过细胞分裂产生的表观遗传变化。环境暴露导致的持续表观遗传变化包括胞嘧啶的DNA甲基化的获得或丧失，这可能影响基因表达。在本研究中，我们比较了全身质子照射对小鼠海马和左心室的长期表观遗传效应。我们使用了一项无偏的全基因组DNA甲基化研究，涉及ChIP-seq与5-甲基胞嘧啶（5 mC）和5-羟甲基胞嘧啶（5 hmC）的抗体，以确定甲基化水平在单次暴露于质子照射后22周发生变化的DNA区域。我们使用DIP-Seq分析质子照射后全基因组DNA甲基化和羟甲基化的变化。此外，我们使用已发表的RNAseq数据来评估差异甲基化区域是否与基因表达的变化有关。DNA甲基化数据显示了质子照射的组织依赖性效应，并揭示了与已知病理生理过程相关的照射反应的显著主要途径变化。心室中受影响的许多区域映射到涉及心血管功能通路的基因，而海马中受影响的许多区域映射到涉及神经元功能的基因。在心室中，5 hmC的增加与5 mC的降低相关。我们还观察到两个表观遗传标记在心室中减少的区域的空间重叠。在海马中，5 hmC的增加与5 mC增加的区域最显著相关（空间），表明海马5 mC和5 hmC的沉积可能是机械耦合的。结果表明，单次质子照射后DNA甲基化模式的长期变化，这些变化是组织特异性的，并且它们映射到与组织对质子照射的特异性反应一致的途径。此外，结果表明5 mC和5 hmC的变化之间存在新的关系。本文的在线版本（doi：10.1186/s12864-016-2581-x）包含补充材料，可供授权用户使用。
Proton irradiation poses a potential hazard to astronauts during and following a mission, with post-mitotic cells at most risk because they cannot dilute resultant epigenetic changes via cell division. Persistent epigenetic changes that result from environmental exposures include gains or losses of DNA methylation of cytosine, which can impact gene expression. In the present study, we compared the long-term epigenetic effects of whole body proton irradiation in the mouse hippocampus and left ventricle. We used an unbiased genome-wide DNA methylation study, involving ChIP-seq with antibodies to 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) to identify DNA regions in which methylation levels have changed 22 weeks after a single exposure to proton irradiation. We used DIP-Seq to profile changes in genome-wide DNA methylation and hydroxymethylation following proton irradiation. In addition, we used published RNAseq data to assess whether differentially methylated regions were linked to changes in gene expression. The DNA methylation data showed tissue-dependent effects of proton irradiation and revealed significant major pathway changes in response to irradiation that are related to known pathophysiologic processes. Many regions affected in the ventricle mapped to genes involved in cardiovascular function pathways, whereas many regions affected in the hippocampus mapped to genes involved in neuronal functions. In the ventricle, increases in 5hmC were associated with decreases in 5mC. We also observed spatial overlap for regions where both epigenetic marks decreased in the ventricle. In hippocampus, increases in 5hmC were most significantly correlated (spatially) with regions that had increased 5mC, suggesting that deposition of hippocampal 5mC and 5hmC may be mechanistically coupled. The results demonstrate long-term changes in DNA methylation patterns following a single proton irradiation, that these changes are tissue specific, and that they map to pathways consistent with tissue specific responses to proton irradiation. Further, the results suggest novel relationships between changes in 5mC and 5hmC. The online version of this article (doi:10.1186/s12864-016-2581-x) contains supplementary material, which is available to authorized users.