Department of Neurobiology, Interdisciplinary Center for Neurosciences (IZN), Heidelberg University, INF 366, 69120, Heidelberg, Germany.
Institute of Pharmacology, Heidelberg University, INF 366, 69120, Heidelberg, Germany.
Nat Commun. 2022 Feb 15;13(1):875. doi: 10.1038/s41467-022-28357-x.
Persistent pain is sustained by maladaptive changes in gene transcription resulting in altered function of the relevant circuits; therapies are still unsatisfactory. The epigenetic mechanisms and affected genes linking nociceptive activity to transcriptional changes and pathological sensitivity are unclear. Here, we found that, among several histone deacetylases (HDACs), synaptic activity specifically affects HDAC4 in murine spinal cord dorsal horn neurons. Noxious stimuli that induce long-lasting inflammatory hypersensitivity cause nuclear export and inactivation of HDAC4. The development of inflammation-associated mechanical hypersensitivity, but neither acute nor basal sensitivity, is impaired by the expression of a constitutively nuclear localized HDAC4 mutant. Next generation RNA-sequencing revealed an HDAC4-regulated gene program comprising mediators of sensitization including the organic anion transporter OAT1, known for its renal transport function. Using pharmacological and molecular tools to modulate OAT1 activity or expression, we causally link OAT1 to persistent inflammatory hypersensitivity in mice. Thus, HDAC4 is a key epigenetic regulator that translates nociceptive activity into sensitization by regulating OAT1, which is a potential target for pain-relieving therapies.
持续性疼痛是由基因转录的适应性改变持续引起的，导致相关回路的功能改变；治疗方法仍不尽如人意。将伤害性活动与转录变化和病理性敏感性联系起来的表观遗传机制和受影响的基因尚不清楚。在这里，我们发现，在几种组蛋白去乙酰化酶（HDACs）中，突触活动特异性地影响小鼠脊髓背角神经元中的 HDAC4。引起持久炎症性超敏反应的有害刺激会导致 HDAC4 的核输出和失活。炎症相关机械性超敏反应的发展受到组成型核定位 HDAC4 突变体表达的损害，但急性和基础敏感性不受损害。下一代 RNA 测序显示了一个由 HDAC4 调节的基因程序，其中包括敏化的介质，包括有机阴离子转运蛋白 OAT1，其以肾脏转运功能而闻名。使用药理学和分子工具来调节 OAT1 的活性或表达，我们将 OAT1 与小鼠的持续性炎症性超敏反应联系起来。因此，HDAC4 是一种关键的表观遗传调节剂，通过调节 OAT1 将伤害性活动转化为敏化，OAT1 是缓解疼痛治疗的潜在靶点。
