Novel histone modifications in microglia derived from a mouse model of chronic pain
Novel histone modifications in microglia derived from a mouse model of chronic pain
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DOI：
10.1002/pmic.202100137
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发表时间：
2022-01
期刊：
影响因子：
3.4
通讯作者：
Ping Zhang;Jennifer Guergues;Amy R. Alleyne;Thomas J. Cirino;Owen Nadeau;Ariana M. Figueroa;Heather M. Stacy;Takayoshi Suzuki;J. McLaughlin;S. Stevens;Bin Liu
中科院分区：
文献类型：
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作者：
Ping Zhang;Jennifer Guergues;Amy R. Alleyne;Thomas J. Cirino;Owen Nadeau;Ariana M. Figueroa;Heather M. Stacy;Takayoshi Suzuki;J. McLaughlin;S. Stevens;Bin Liu
小胶质细胞作为中枢神经系统的常驻免疫细胞，在维持中枢神经系统的稳态中起着重要的作用。小胶质细胞的失调与慢性疼痛的发生和维持有关。然而，相关的分子途径仍然不明确。在这项研究中，我们使用基于质谱的蛋白质组学方法来筛选从对照和顺铂诱导的神经性疼痛成年C57BL/6J雄性小鼠脑分离的小胶质细胞中组蛋白修饰的潜在变化。我们发现了几种与疼痛相关的新型小胶质组蛋白修饰，包括统计学上显著降低组蛋白H3.1赖氨酸27单甲基化（H3.1 k27me1，对照组的54.8%）和H3赖氨酸56三甲基化（对照组的7.5%），以及H3酪氨酸41硝化增加的趋势。我们进一步研究了H3.1K27me1的功能作用，发现用1-10 μM的NCDM - 64（赖氨酸去甲基化酶7A的有效选择性抑制剂，负责H3K27me1的去甲基化）连续4天处理培养的小胶质细胞，剂量依赖性地提高了其水平，10 μM的NCDM - 64与对照细胞相比增加了两倍以上。此外，在顺铂治疗前用NCDM - 64（10或25 mg/kg/day， i.p）预处理小鼠，可防止小鼠神经性疼痛的发生。在与慢性疼痛相关的小胶质细胞中特异性染色质标记的鉴定可能会对小胶质细胞对疼痛的发展和维持的贡献产生关键的见解，并为开发新的非阿片类药物治疗慢性疼痛的有效管理开辟新的途径。
As the resident immune cells in the central nervous system, microglia play an important role in the maintenance of its homeostasis. Dysregulation of microglia has been associated with the development and maintenance of chronic pain. However, the relevant molecular pathways remain poorly defined. In this study, we used a mass spectrometry‐based proteomic approach to screen potential changes of histone protein modifications in microglia isolated from the brain of control and cisplatin‐induced neuropathic pain adult C57BL/6J male mice. We identified several novel microglial histone modifications associated with pain, including statistically significantly decreased histone H3.1 lysine 27 mono‐methylation (H3.1K27me1, 54.8% of control) and H3 lysine 56 tri‐methylation (7.5% of control), as well as a trend suggesting increased H3 tyrosine 41 nitration. We further investigated the functional role of H3.1K27me1 and found that treatment of cultured microglial cells for 4 consecutive days with 1–10 μM of NCDM‐64, a potent and selective inhibitor of lysine demethylase 7A, an enzyme responsible for the demethylation of H3K27me1, dose‐dependently elevated its levels with a greater than a two‐fold increase observed at 10 μM compared to vehicle‐treated control cells. Moreover, pretreatment of mice with NCDM‐64 (10 or 25 mg/kg/day, i.p.) prior to cisplatin treatment prevented the development of neuropathic pain in mice. The identification of specific chromatin marks in microglia associated with chronic pain may yield critical insight into the contribution of microglia to the development and maintenance of pain, and opens new avenues for the development of novel nonopioid therapeutics for the effective management of chronic pain.