Recent studies have shown that epigenetic

Recent studies have shown that epigenetic modification is involved in neuropathic pain. For instance, peripheral noxious stimulation changes DNA methylation and histone modifications, which are related to pain hypersensitivity under chronic pain conditions [8]. Importantly, the epigenetic abnormality is also observed in the spinal cord during neuropathic pain [9]. Changes in histone lysine methylation status are a consequence of the imbalance of histone lysine methyltransferases or demethylases [10]. The JMJD (JmjC domain-containing) proteins, is composed of 30 members in humans based on the presence of the roughly 150 amino acid–long JmjC domain [11]. JMJD2 proteins (JMJD2A-JMJD2D) family is the largest JMJD subfamilies that attracted much attention recently. The members of the JMJD2 family are capable of recognizing and demethylating di- and tri-methylated H3K9 (H3K9me2/3) and H3K36 (H3K36me2/3) [10]. Among the members, JMJD2A is one of the most studied ones. A major study focus on JMJD2A has been in transcription regulation, where it may either stimulate or repress gene transcription. JMJD2A forms complexes with both the androgen and estrogen receptor (ER) and stimulates their activity, which relies largely upon JMJD2A catalytic activity [12], [13]. Diverse physiological or pathological functions of JMJD2A have been identified, especially in development [14], and in diseases such as cancer and cardiovascular diseases [15], [16]. For instance, JMJD2A regulates neural crest specification [14]. However, the roles of JMJD2A in neuropathic pain remains unknown. In the present work, we aimed to investigate the function of JMJD2A in chronic neuropathic pain and found that JMJD2A promoted the hypersensitivity of neuropathic pain by epigenetically regulating the expression of Bdnf. The expression of JMJD2A is increased in neurons of two models of neuropathic pain, which are partially due to the regulation of 5-HT. JMJD2A bound to the promoter of Bdnf and demethylates H3K9me3 and H3K36me3 to activate the expression of Bdnf and facilitates the development of neuropathic pain.
Materials and methods
Results
Discussion In the present study, we found that the histone demethylase JMJD2A regulated the expression of Bdnf and participated in neuropathic pain. The mRNA and protein levels of Jmjd2a were significantly upregulated in neurons of mice with neuropathic pain induced by CCI or SNI. 5-HT mediated the upregulation of Bdnf and the demethylase JMJD2A. We found that JMJD2A could bind to the promoter of Bdnf and demethylated H3K9me3 and H3K36me3 to promote the expression of Bdnf induced by neuropathic pain and 5-HT. Finally, we provided evidence that Jmjd2a knockout repressed neuropathic pain in mice. Epigenetic irak1 play essential roles in neuropathic pain. Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase. Numerous reports have shown that CDK5 critically contributes to the induction and maintenance of chronic pain induced by peripheral inflammation and nerve injury [23], [24]. Phosphorylation of cAMP-response element binding protein (CREB) and its occupancy at the promoter region of the Cdk5 is increased in the dorsal horn, which leads to increased histone H4 acetylation at the promoter region of the Cdk5 and the induction of transcription of Cdk5[25]. Another example is the glutamic acid decarboxylase 65 (GAD65). Inflammatory and neuropathic pain epigenetically suppresses Gad2 (encoding GAD65) transcription through histone deacetylase (HDAC)-mediated histone hypoacetylation, resulting in impaired γ-aminobutyric acid (GABA) synaptic inhibition [26]. Furthermore, p300 exerts an epigenetic role in chronic neuropathic pain through its acetyltransferase activity in rats following CCI [27]. Here we reported that histone methylation also participated in neuropathic pain in mice. JMJD2A is a histone demethylase that functions as a trimethylation-specific demethylase, converting specific trimethylated histone on H3K9me3 and H3K36me3 to dimethylated residues to monomethyl, and as a transcriptional repressor or activator dependently [11]. We induced neuropathic pain in mice by CCI and SNI surgery and analyzed the mRNA and protein level of Jmjd2a in neurons at day seven post surgery. Significantly, we found that JMJD2A expression was significantly up-regulated in neurons from mice with neuropathic pain. The up-regulation of JMJD2A was mediated by 5-HT, which acts through 5-HT receptors and contributes to neuropathic pain [3]. However, further studies are needed to explore the potential mechanism underlying 5-HT-mediated JMJD2A up-regulation during neuropathic pain. We knocked out Jmjd2a in the neurons of mice and analyzed the effects of JMJD2A in neuropathic pain induced by CCI and SNI. We measured the mechanical sensitivity of mice before and posted injury. CCI and SNI could significantly increase mechanical sensitivity with reduced paw withdraw threshold. Interestingly, Jmjd2a knockout blocked CCI or SNI induced mechanical sensitivity. Taken together, Jmjd2a expression is up-regulated during neuropathic pain induced by CCI and SNI, which may be due to the effect of 5-HT. Furthermore, Jmjd2a is required for the development of neuropathic pain induced by CCI and SNI. In this regard, JMJD2A could be a potential target for treatment of neuropathic pain. The inhibitor of JMJD2A, such as IOX1 [28], could be investigated for its potential as a drug for treatment of neuropathic pain. A previous work reported that JMJD2A is expressed in the forming neural folds and loss of JMJD2A function causes dramatic down-regulation of neural crest specifier genes analyzed by multiplex NanoString and in situ hybridization [14]. Therefore, these findings support that JMJD2A is critically required for development and stress response.