Molecular basis of FAAH-OUT-associated human pain insensitivity.
Molecular basis of FAAH-OUT-associated human pain insensitivity.
复制标题
DOI：
10.1093/brain/awad098
复制
发表时间：
2023-09-01
期刊：
影响因子：
14.5
通讯作者：
Cox, James J.
中科院分区：
文献类型：
--
作者：
Mikaeili, Hajar;Habib, Abdella M.;Yeung, Charlix Wai-Lok;Santana-Varela, Sonia;Luiz, Ana P.;Panteleeva, Kseniia;Zuberi, Sana;Athanasiou-Fragkouli, Alkyoni;Houlden, Henry;Wood, John N.;Okorokov, Andrei L.;Cox, James J.
慢性疼痛影响着全世界数百万人，迫切需要新的治疗方法。确定新型镇痛策略的一种方法是了解导致人类遗传性疼痛不敏感疾病的生物学功能障碍。在这里，我们报道了最近发现的脑和背根神经节表达的FAAH-外长链非编码RNA （lncRNA）基因是如何调节邻近的内源性大麻素系统关键基因FAAH的，该基因编码大麻酰胺降解脂肪酸酰胺水解酶。该基因是通过研究一个焦虑减少和伤口快速愈合的疼痛不敏感患者而发现的。我们证明FAAH- out lncRNA转录的中断导致FAAH启动子内dnmt1依赖的DNA甲基化。此外，FAAH- out包含一个保守的调控元件FAAH- amp，它作为FAAH表达的增强剂。此外，通过对患者源性细胞的转录组学分析，我们发现了一个因FAAH-FAAH-OUT轴断裂而失调的基因网络，从而为理解所观察到的人类表型提供了一致的机制基础。鉴于FAAH是治疗疼痛、焦虑、抑郁和其他神经系统疾病的潜在靶点，对FAAH- out基因调控作用的新认识为未来基因和小分子疗法的发展提供了一个平台。Mikaeili等人确定了faah - out相关疼痛不敏感的分子基础，其中无痛伴随着焦虑减少和伤口愈合加速。FAAH- out长链非编码RNA基因通过两种转录依赖机制调节FAAH的表达，为未来的基因治疗提供了平台。
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-expressed FAAH-OUT long 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 gene FAAH, which encodes the anandamide-degrading fatty acid amide hydrolase enzyme. We demonstrate that the disruption in FAAH-OUT lncRNA transcription leads to DNMT1-dependent DNA methylation within the FAAH promoter. In addition, FAAH-OUT contains a conserved regulatory element, FAAH-AMP, that acts as an enhancer for FAAH expression. Furthermore, using transcriptomic analyses in patient-derived cells we have uncovered a network of genes that are dysregulated from disruption of the FAAH-FAAH-OUT axis, thus providing a coherent mechanistic basis to understand the human phenotype observed. Given that FAAH is a potential target for the treatment of pain, anxiety, depression and other neurological disorders, this new understanding of the regulatory role of the FAAH-OUT gene provides a platform for the development of future gene and small molecule therapies. Mikaeili et al. identify the molecular basis of FAAH-OUT-associated pain insensitivity, in which painlessness is accompanied by reduced anxiety and accelerated wound healing. The FAAH-OUT long non-coding RNA gene regulates FAAH expression via two transcription-dependent mechanisms, providing a platform for future gene therapy.
登录
查看更多内容
DOI：
10.1016/j.tig.2016.10.002
发表时间：
2016-12
期刊：
Trends in genetics : TIG
影响因子：
--
作者：
Chédin F
通讯作者：
Chédin F
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1124/jpet.111.180257
发表时间：
2011-07-01
影响因子：
3.5
作者：
Ahn, Kay;Smith, Sarah E.;Cravatt, Benjamin F.
通讯作者：
Cravatt, Benjamin F.
影响因子：
3.6
作者：
Ehrlich AT;Semache M;Couvineau P;Wojcik S;Kobayashi H;Thelen M;Gross F;Hogue M;Le Gouill C;Darcq E;Bouvier M;Kieffer BL
通讯作者：
Kieffer BL
R环的形成是未甲基化的人类CpG岛启动子的独特特征。
影响因子：
16
作者：
Ginno PA;Lott PL;Christensen HC;Korf I;Chédin F
通讯作者：
Chédin F