Genome-wide Analysis of Histone H3 Lysine 27 Trimethylation Profiles in Sciatic Nerve of Chronic Constriction Injury Rats
Genome-wide Analysis of Histone H3 Lysine 27 Trimethylation Profiles in Sciatic Nerve of Chronic Constriction Injury Rats
复制标题
慢性缩窄性损伤大鼠坐骨神经组蛋白 H3 赖氨酸 27 三甲基化谱的全基因组分析
DOI：
10.1007/s11064-023-03879-y
复制
发表时间：
2023-02-10
影响因子：
4.4
通讯作者：
Wang，Zhaojin
中科院分区：
文献类型：
--
作者：
Chen，Shuhui;Gu，Xinpei;Wang，Zhaojin
组蛋白H3赖氨酸27三甲基化（H3 K27 me 3）是雪旺细胞（Schwann cells，SC）中最重要的染色质修饰之一，与损伤激活的基因表达有关。然而，全基因组H3 K27 me 3富集在神经病理性疼痛的发展中的改变仍然是未知的。在这里，我们应用染色质免疫沉淀测序（ChIP-seq）的方法，以确定在慢性压迫性损伤（CCI）大鼠坐骨神经H3 K27 me 3的差异富集的变化和潜在的分子机制的发展神经病理性疼痛。我们的结果表明，CCI增加了坐骨神经中展示H3 K27甲基转移酶增强子zeste同源物2（EZH 2）和H3 K27 me 3的SC的数量。ChIP-seq数据显示，CCI显著改变了坐骨神经中基因启动子上的H3 K27 me 3富集。生物信息学分析表明，获得H3 K27 me 3的基因主要与细胞增殖调控、应激反应和氧化还原过程有关。失去该标记的基因在神经元生成、MAPK、cAMP以及ERBB信号通路中富集。重要的是，IL 1A、CCL 2、NOS 2、S100 A8、BDNF、GDNF、ERBB 3和C3被鉴定为神经病理性疼痛的关键基因。CCI导致坐骨神经中关键基因的显著上调。EZH 2抑制剂逆转CCI诱导的H3 K27 me 3和关键基因蛋白水平的增加，这伴随着减轻CCI大鼠的机械异常性疼痛和热痛觉过敏。这些结果表明，在SC中具有H3 K27 me 3差异富集的基因在各种细胞过程和途径中发挥作用，并且许多与周围神经损伤后的神经性疼痛有关。
The histone H3 lysine 27 trimethylation (H3K27me3) is one of the most important chromatin modifications, which is associated with injury-activated gene expression in Schwann cells (SCs). However, the alteration of genome-wide H3K27me3 enrichments in the development of neuropathic pain is still unknown. Here, we applied the chromatin immunoprecipitation sequencing (ChIP-seq) approach to identify the alteration of differential enrichments of H3K27me3 in chronic constriction injury (CCI) sciatic nerve of rats and potential molecular mechanisms underlying the development of neuropathic pain. Our results indicated that CCI increased the numbers of SCs displaying H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) and H3K27me3 in the sciatic nerve. ChIP-seq data showed that CCI significantly changed H3K27me3 enrichments on gene promoters in the sciatic nerve. Bioinformatics analyses exhibited that genes gaining H3K27me3 were mostly associated with regulation of cell proliferation, response to stress and oxidation-reduction process. Genes losing this mark were enriched in neuronal generation, and MAPK, cAMP as well as ERBB signaling pathways. Importantly, IL1A, CCL2, NOS2, S100A8, BDNF, GDNF, ERBB3 and C3 were identified as key genes in neuropathic pain. CCI led to significant upregulation of key genes in the sciatic nerve. EZH2 inhibitor reversed CCI-induced increases of H3K27me3 and key gene protein levels, which were accompanied by relieved mechanical allodynia and thermal hyperalgesia in CCI rats. These results indicate that genes with differential enrichments of H3K27me3 in SCs function in various cellular processes and pathways, and many are linked to neuropathic pain after peripheral nerve injury.