Molecular basis of FAAH-OUT -associated human pain insensitivity
Molecular basis of FAAH-OUT -associated human pain insensitivity
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FAAH-OUT 相关人类疼痛不敏感的分子基础
DOI：
10.1101/2022.10.20.513066
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Mikaeili H
中科院分区：
文献类型：
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作者：
Mikaeili H
慢性疼痛影响着全世界数百万人，迫切需要新的治疗方法。确定新的镇痛策略的一种方法是了解导致人类遗传性疼痛不敏感性疾病的生物学功能障碍。在这里，我们报告了最近发现的大脑和背根神经节表达的FAAH-OUT长非编码RNA（lncRNA）基因，该基因是从研究焦虑减少和伤口快速愈合的疼痛不敏感患者中发现的，它如何调节邻近的关键内源性大麻素系统基因FAAH，我们证明FAAH-OUTlncRNA转录的破坏导致DNMT1-FAAH启动子内依赖的DNA甲基化。此外，FAAH-OUT包含一个保守的调节元件FAAH-AMP，它作为FAAH表达的增强子。此外，在患者来源的细胞中使用转录组学分析，我们发现了一个因FAAH-FAAH-OUT轴的破坏而失调的基因网络，从而为理解所观察到的人类表型提供了一个连贯的机制基础。抑郁症和其他神经系统疾病，这一对FAAH-OUT基因调节作用的新认识为未来基因和小分子疗法的发展提供了平台。
Chronic pain affects millions of people worldwide and new treatments are needed urgently. One way to identify novel analgesic strategies is to understand the biological dysfunctions that lead to human inherited pain insensitivity disorders. Here we report how the recently discovered brain and dorsal root ganglia-expressedFAAH-OUTlong non-coding RNA (lncRNA) gene, which was found from studying a pain-insensitive patient with reduced anxiety and fast wound healing, regulates the adjacent key endocannabinoid system geneFAAH, which encodes the anandamide-degrading fatty acid amide hydrolase enzyme.We demonstrate that the disruption inFAAH-OUTlncRNA transcription leads to DNMT1-dependent DNA methylation within theFAAHpromoter. In addition,FAAH-OUTcontains a conserved regulatory element, FAAH-AMP, that acts as an enhancer forFAAHexpression.Furthermore, using transcriptomic analyses in patient-derived cells we have uncovered a network of genes that are dysregulated from disruption of theFAAH-FAAH-OUTaxis, thus providing a coherent mechanistic basis to understand the human phenotype observed.Given thatFAAHis a potential target for the treatment of pain, anxiety, depression and other neurological disorders, this new understanding of the regulatory role of theFAAH-OUTgene provides a platform for the development of future gene and small molecule therapies.