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A trans-eQTL network regulates osteoclast multinucleation and bone mass

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 knockout mice displayed abnormal bone phenotypes. We report opposing 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 multinucleation and bone mass.
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https://hal-pasteur.archives-ouvertes.fr/pasteur-03696673
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Submitted on : Thursday, June 16, 2022 - 10:25:52 AM
Last modification on : Friday, June 17, 2022 - 3:07:00 AM

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Marie Pereira, Jeong-Hun Ko, John Logan, Hayley Protheroe, Kee-Beom Kim, et al.. A trans-eQTL network regulates osteoclast multinucleation and bone mass. eLife, eLife Sciences Publication, 2020, 9, pp.e55549. ⟨10.7554/eLife.55549⟩. ⟨pasteur-03696673⟩

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