Molecular basis ofFAAH-OUT-associated human pain insensitivity

Chronic pain affects millions of people worldwide. Studying pain insensitive individuals helps to identify novel analgesic strategies. Here we report how the recently discovered FAAH-OUT lncRNA-encoding 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 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 and a platform for development of future gene and small molecule therapies.