A trans-eQTL network regulates osteoclast multinucleation and bone mass

Pereira, M.; Ko, J.-H.; Logan, J.; Protheroe, H.; Kim, K.-B.; Tan, A. L. M.; Park, K.-S.; Rotival, M.; Petretto, E.; Bassett, J. H. D.; Williams, G. R.; Behmoaras, J.

doi:10.1101/2020.02.13.947705

bioRxiv · 10.1101/2020.02.13.947705

A trans-eQTL network regulates osteoclast multinucleation and bone mass

Pereira, M.·Ko, J.-H.·Logan, J.·Protheroe, H.·Kim, K.-B.·Tan, A. L. M.·Park, K.-S.·Rotival, M.·Petretto, E.·Bassett, J. H. D.·Williams, G. R.·Behmoaras, J.

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Abstract

Functional characterisation of cell-type specific regulatory networks is key to establish a causal link between genetic variation and phenotype. The osteoclast offers a unique model for interrogating the contribution of co-regulated genes to in vivo phenotype as its multinucleation and resorption activities determine quantifiable skeletal traits. Here we took advantage of a trans-regulated gene network (MMnet, macrophage multinucleation network) which we found to be significantly enriched for GWAS variants associated with bone-related phenotypes. We found that the network hub gene Bcat1 and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (Pik3cb-/-, Atp8b2+/-, Igsf8-/-, Eml1-/-, Appl2-/-, Deptor-/-) and myeloid-specific Slc40a1{Delta}LysMCre knockout mice displayed abnormal bone phenotypes. We report antagonizing effects of MMnet genes on bone mass in mice and osteoclast multinucleation/resorption in humans with strong correlation between the two. These results identify MMnet as a functionally conserved network that regulates osteoclast fusion and bone mass. Impact statementWe took advantage of the osteoclast whose multinucleation properties correlate with bone mass. We show that a trans-regulated gene network (MMnet) controls skeletal homeostasis through osteoclast multinucleation and function.

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Pereira, M., Ko, J.-H., Logan, J., Protheroe, H., Kim, K.-B., Tan, A. L. M., Park, K.-S., Rotival, M., Petretto, E., Bassett, J. H. D., Williams, G. R., Behmoaras, J.. 2020-02-13. A trans-eQTL network regulates osteoclast multinucleation and bone mass. https://doi.org/10.1101/2020.02.13.947705

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