背根神经节中转录因子ZNF382调控神经病理性疼痛的机制研究

神经病理性疼痛是医学研究领域的难点，对其机制和治疗方法的研究目前需要寻找新的方向和突破点。我们前期研究发现锌指蛋白转录因子ZNF382在神经病理性疼痛模型中明显减少，过表达ZNF382可以显著缓解痛行为；测序发现ZNF382通过与基因启动子上游远端序列结合，可以抑制CXCL13等致痛基因表达。基于文献和前期结果，我们提出如下科学假说：外周神经损伤引起ZNF382表达降低，导致ZNF382与下游基因的远端功能元件——沉默子（silencer）结合减少，影响ZNF382招募HDAC1和SETDB1形成转录抑制复合体，导致启动子区组蛋白乙酰化和甲基化修饰发生改变，从而影响下游基因转录，最终引起神经病理性疼痛。因此本研究拟采用DRG显微注射技术、基因修饰小鼠，以及形态学、分子生物学和行为学等工具和方法证明上述假说。有望揭示一种新的神经病理性疼痛发生发展的表观调控机制。

Neuropathic pain is a debilitating condition and it’s necessary and urgent to find novel directions or targets for the mechanism and therapy. Our pilot finding demonstrated that Zinc Finger Transcription Factor ZNF382 was decreased significantly in neuropathic pain model and the rescue of ZNF382 obviously alleviated the pain behavior. Our ChIP-seq and RNA-seq data showed that ZNF382 bound to the distal sequence upstream of promoter which suppressed the expression of pain-related genes like CXCL13. Based on the literatures and our preliminary data, we hypothesize that peripheral nerve injury-induced down-regulation in ZNF382 causes its decrease in binding to distal functional element, silencer, of downstream target genes. It decreases the recruitment of HDAC1 and SETDB1 in charge of the level of ac-H3 and H3K9me3 in promoter, initiates the transcription of downstream genes and finally triggers neuropathic pain. This study will carry out multidisciplinary approaches and tools to investigate the proposal described above, including DRG microinjection, transgenic mice, morphology, molecular biology and behavioral testing, so as to explore and unravel a new epigenetic regulatory mechanism of neuropathic pain.