| Popis: |
Chronic pain affects millions of people worldwide. Studying pain insensitive individuals helps to identify novel analgesic strategies. Here we report how the recently discoveredFAAH-OUTlncRNA-encoding 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 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 and a platform for development of future gene and small molecule therapies. |
