DNA Hydroxymethylation by Ten-eleven Translocation Methylcytosine Dioxygenase 1 and 3 Regulates Nociceptive Sensitization in a Chronic Inflammatory Pain Model
DNA Hydroxymethylation by Ten-eleven Translocation Methylcytosine Dioxygenase 1 and 3 Regulates Nociceptive Sensitization in a Chronic Inflammatory Pain Model
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11-11 易位甲基胞嘧啶双加氧酶 1 和 3 的 DNA 羟甲基化调节慢性炎症疼痛模型中的伤害性敏化
DOI：
10.1097/aln.0000000000001632
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发表时间：
2017-07-01
期刊：
影响因子：
8.8
通讯作者：
Cao, Jun-Li
中科院分区：
文献类型：
--
作者：
Pan, Zhiqiang;Xue, Zhou-Ya;Cao, Jun-Li
背景资料：10 - 11易位甲基胞嘧啶双加氧酶将DNA中的5-甲基胞嘧啶转化为5-羟甲基胞嘧啶，在基因转录中起重要作用。尽管5-羟甲基胞嘧啶在哺乳动物神经元中富集，但其在伤害性信息处理中的调节功能尚不清楚。研究方法：在用完全弗氏佐剂处理的小鼠的脊髓中测量5-羟甲基胞嘧啶和10 - 11易位甲基胞嘧啶双加氧酶的总体水平。采用免疫印迹、免疫组织化学和行为学测试来探索下游10 - 11易位甲基胞嘧啶双加氧酶依赖的信号通路。结果如下：完全弗氏镇痛剂诱导的伤害性感受增加脊髓5-羟甲基胞嘧啶的平均水平（± SD）（178 ± 34 vs. 100 ± 21; P = 0.0019），10 - 11易位甲基胞嘧啶双加氧酶-1（0.52 ± 0.11 vs.0.36 ± 0.064; P = 0.0088），10 - 11易位甲基胞嘧啶双加氧酶-3（0.61 ± 0.13 vs. 0.39 ± 0.08; P = 0.0083）与对照小鼠（n = 6/组）中的水平相比。敲低10 - 11易位甲基胞嘧啶双加氧酶-1或10 - 11易位甲基胞嘧啶双加氧酶-3可减轻热痛觉过敏和机械异常性疼痛，而过表达胞嘧啶则可减轻热痛觉过敏和机械异常性疼痛（n = 6/组）。脊髓10 - 11易位甲基胞嘧啶双加氧酶-1和10 - 11易位甲基胞嘧啶双加氧酶-3的下调也逆转了Fos表达的增加（123 ± 26 vs. 294 ± 6; P = 0.0031; 140 ± 21 vs. 294 ± 60; P = 0.0043; n = 6/组），Stat 3启动子中的5-羟甲基胞嘧啶水平（分别为75 ± 16.1 vs. 156 ± 28.9; P = 0.0043;和91 ± 19.1 vs. 156 ± 28.9; P = 0.0066; n = 5/组），以及随后的Stat 3表达（分别为93 ± 19.6 vs. 137 ± 27.5; P = 0.035;和72 ± 15.2 vs. 137 ± 27.5; P = 0.0028; n = 5/组）。结论：这项研究揭示了一种新的表观遗传机制，10 - 11易位甲基胞嘧啶双加氧酶-1和10 - 11易位甲基胞嘧啶双加氧酶-3在调制脊髓伤害性信息通过靶向Stat 3。
Background: Ten-eleven translocation methylcytosine dioxygenase converts 5-methylcytosine in DNA to 5-hydroxymethylcytosine, which plays an important role in gene transcription. Although 5-hydroxymethylcytosine is enriched in mammalian neurons, its regulatory function in nociceptive information processing is unknown. Methods: The global levels of 5-hydroxymethylcytosine and ten-eleven translocation methylcytosine dioxygenase were measured in spinal cords in mice treated with complete Freund’s adjuvant. Immunoblotting, immunohistochemistry, and behavioral tests were used to explore the downstream ten-eleven translocation methylcytosine dioxygenase-dependent signaling pathway. Results: Complete Freund’s adjuvant-induced nociception increased the mean levels (± SD) of spinal 5-hydroxymethylcytosine (178 ± 34 vs. 100 ± 21; P = 0.0019), ten-eleven translocation methylcytosine dioxygenase-1 (0.52 ± 0.11 vs. 0.36 ± 0.064; P = 0.0088), and ten-eleven translocation methylcytosine dioxygenase-3 (0.61 ± 0.13 vs. 0.39 ± 0.08; P = 0.0083) compared with levels in control mice (n = 6/group). The knockdown of ten-eleven translocation methylcytosine dioxygenase-1 or ten-eleven translocation methylcytosine dioxygenase-3 alleviated thermal hyperalgesia and mechanical allodynia, whereas overexpression cytosinethem in naïve mice (n = 6/group). Down-regulation of spinal ten-eleven translocation methylcytosine dioxygenase-1 and ten-eleven translocation methylcytosine dioxygenase-3 also reversed the increases in Fos expression (123 ± 26 vs. 294 ± 6; P = 0.0031; and 140 ± 21 vs. 294 ± 60; P = 0.0043, respectively; n = 6/group), 5-hydroxymethylcytosine levels in the Stat3 promoter (75 ± 16.1 vs. 156 ± 28.9; P = 0.0043; and 91 ± 19.1 vs. 156 ± 28.9; P = 0.0066, respectively; n = 5/group), and consequent Stat3 expression (93 ± 19.6 vs. 137 ± 27.5; P = 0.035; and 72 ± 15.2 vs. 137 ± 27.5; P = 0.0028, respectively; n = 5/group) in complete Freund’s adjuvant-treated mice. Conclusions: This study reveals a novel epigenetic mechanism for ten-eleven translocation methylcytosine dioxygenase-1 and ten-eleven translocation methylcytosine dioxygenase-3 in the modulation of spinal nociceptive information via targeting of Stat3.