Newly Published
Pain Medicine  |   April 2017
DNA Hydroxymethylation by Ten-eleven Translocation Methylcytosine Dioxygenase 1 and 3 Regulates Nociceptive Sensitization in a Chronic Inflammatory Pain Model
Author Notes
  • From Jiangsu Province Key Laboratory of Anesthesiology (Z.P., Z.-Y.X., G.-F.L., M.-L.S., M.Z., L.-Y.H., Q.-Q.T., L.-J.Z., J.-L.C.) and Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology (Z.P., Z.-Y.X., G.-F.L., M.-L.S., M.Z., L.-Y.H., Q.-Q.T., L.-J.Z., J.-L.C.), Xuzhou Medical University, Xuzhou; and Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou (J.-L.C.), China.
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • Z.P., Z.-Y.X., and G.-F.L. contributed equally to this article.
    Z.P., Z.-Y.X., and G.-F.L. contributed equally to this article.×
  • Submitted for publication August 4, 2016. Accepted for publication March 2, 2017.
    Submitted for publication August 4, 2016. Accepted for publication March 2, 2017.×
  • Acknowledgments: The authors thank Hai-Lei Ding, M.D., Ph.D., Wen Shen, M.D., Lianshen Zhong, M.D., Ph.D., Yanqiang Li, Ph.D., and Zi-Peng Liu, Ph.D. (Department of Anesthesiology, The University of Hong Kong) for help with statistical analyses, informatics analyses, and for constructive discussions.
    Acknowledgments: The authors thank Hai-Lei Ding, M.D., Ph.D., Wen Shen, M.D., Lianshen Zhong, M.D., Ph.D., Yanqiang Li, Ph.D., and Zi-Peng Liu, Ph.D. (Department of Anesthesiology, The University of Hong Kong) for help with statistical analyses, informatics analyses, and for constructive discussions.×
  • Research Support: The study was supported by grants from the National Natural Science Foundation of China (Nos. 81230025, 81671096, 81271231, and 31500855; Peking, China), the Key Project of the Natural Science Foundation of Jiangsu Education Department (No. 15KJA320004; Nanjing, Jiangsu, China), the Qing Lan Project (Nanjing, Jiangsu, China), the Six Talent Summit Project (Nanjing, Jiangsu, China), the 333 High-level Personnel Training Project (Nanjing, Jiangsu, China), the Jiangsu Provincial Special Program of Medical Science (BL2014029; Nanjing, Jiangsu, China), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Nanjing, Jiangsu, China).
    Research Support: The study was supported by grants from the National Natural Science Foundation of China (Nos. 81230025, 81671096, 81271231, and 31500855; Peking, China), the Key Project of the Natural Science Foundation of Jiangsu Education Department (No. 15KJA320004; Nanjing, Jiangsu, China), the Qing Lan Project (Nanjing, Jiangsu, China), the Six Talent Summit Project (Nanjing, Jiangsu, China), the 333 High-level Personnel Training Project (Nanjing, Jiangsu, China), the Jiangsu Provincial Special Program of Medical Science (BL2014029; Nanjing, Jiangsu, China), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (Nanjing, Jiangsu, China).×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence to Dr. Cao: Jiangsu Province Key Laboratory of Anesthesiology, Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, Jiangsu, PR China. caojl0310@aliyun.com. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Pain Medicine
Pain Medicine   |   April 2017
DNA Hydroxymethylation by Ten-eleven Translocation Methylcytosine Dioxygenase 1 and 3 Regulates Nociceptive Sensitization in a Chronic Inflammatory Pain Model
Anesthesiology Newly Published on April 27, 2017. doi:10.1097/ALN.0000000000001632
Anesthesiology Newly Published on April 27, 2017. doi:10.1097/ALN.0000000000001632
Abstract

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.