Tissue-Specific Methylation of Long Interspersed Nucleotide Element-1 of Homo Sapiens (L1Hs) During Human Embryogenesis and Roles in Neural Tube Defects.
Tissue-Specific Methylation of Long Interspersed Nucleotide Element-1 of Homo Sapiens (L1Hs) During Human Embryogenesis and Roles in Neural Tube Defects.
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DOI：
10.2174/1566524015666150630130229
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发表时间：
2015-05
影响因子：
2.5
通讯作者：
L. Wang;S. Chang;J. Guan;S. Shangguan;X. Lu;Z. Wang;L. Wu;J. Zou;H. Zhao;Y. Bao;Z. Qiu;B. Niu;T. Zhang
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文献类型：
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作者：
L. Wang;S. Chang;J. Guan;S. Shangguan;X. Lu;Z. Wang;L. Wu;J. Zou;H. Zhao;Y. Bao;Z. Qiu;B. Niu;T. Zhang
长散布核苷酸元件-1（LINE-1）逆转录转座事件的表观遗传调控在早期发育中起着至关重要的作用。之前我们表明神经元组织中LINE-1低甲基化与神经管缺陷（NTD）的发病机制相关。在此，我们进一步评估了来自死胎NTD胎儿的三个胚层的组织中的LINE-1智人（L1 Hs）甲基化，以定义L1 Hs启动子区域内CpG位点的组织特异性甲基化和位点特异性低甲基化的模式。在胎儿、胎盘和母体外周血的三个胚层谱系中观察到稳定的组织特异性L1 Hs甲基化模式。孕妇外周血L1 Hs甲基化水平最高（64.95%），胎盘组织L1 Hs甲基化水平最低（26.82%）。在NTD和对照组的样本之间，L1 Hs甲基化的降低仅在NTD影响的脑组织中显著，为7.35%，尤其是在女性中（8.98%）。NTD中的L1 Hs低甲基化也与女性中L1 Hs编码的转录本表达水平的显著增加相关（r =-0.846，p = 0.004）。这可能是由于基因组DNA的不稳定性和异常L1 Hs低甲基化导致的染色质可及性的改变，如本研究中用甲基化抑制剂5-Aza处理的HCT-15细胞所示。
Epigenetic regulation of long interspersed nucleotide element-1 (LINE-1) retrotransposition events plays crucial roles during early development. Previously we showed that LINE-1 hypomethylation in neuronal tissues is associated with pathogenesis of neural tube defect (NTD). Herein, we further evaluated LINE-1 Homo sapiens (L1Hs) methylation in tissues derived from three germ layers of stillborn NTD fetuses, to define patterns of tissue specific methylation and site-specific hypomethylation at CpG sites within an L1Hs promoter region. Stable, tissue-specific L1Hs methylation patterns throughout three germ layer lineages of the fetus, placenta, and maternal peripheral blood were observed. Samples from maternal peripheral blood exhibited the highest level of L1Hs methylation (64.95%) and that from placenta showed the lowest (26.82%). Between samples from NTDs and controls, decrease in L1Hs methylation was only significant in NTD-affected brain tissue at 7.35%, especially in females (8.98%). L1Hs hypomethylation in NTDs was also associated with a significant increase in expression level of an L1Hs-encoded transcript in females (r = -0.846, p = 0.004). This could be due to genomic DNA instability and alternation in chromatins accessibility resulted from abnormal L1Hs hypomethylation, as showed in this study with HCT-15 cells treated with methylation inhibitor 5-Aza.