Molecular basis of FAAH-OUT-associated human pain insensitivity

Mikaeili, H.; Habib, A. M.; Yeung, C.; Santana-Varela, S.; Luiz, A. P.; Panteleeva, K.; Zuberi, S.; Athanasiou-Fragkouli, A.; Houlden, H.; Wood, J. N.; Okorokov, A. L.; Cox, J. J.

doi:10.1101/2022.10.20.513066

bioRxiv · 10.1101/2022.10.20.513066

Molecular basis of FAAH-OUT-associated human pain insensitivity

Mikaeili, H.·Habib, A. M.·Yeung, C.·Santana-Varela, S.·Luiz, A. P.·Panteleeva, K.·Zuberi, S.·Athanasiou-Fragkouli, A.·Houlden, H.·Wood, J. N.·Okorokov, A. L.·Cox, J. J.

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Abstract

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.

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Mikaeili, H., Habib, A. M., Yeung, C., Santana-Varela, S., Luiz, A. P., Panteleeva, K., Zuberi, S., Athanasiou-Fragkouli, A., Houlden, H., Wood, J. N., Okorokov, A. L., Cox, J. J.. 2022-10-20. Molecular basis of FAAH-OUT-associated human pain insensitivity. https://doi.org/10.1101/2022.10.20.513066

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