A trans-eQTL network regulates osteoclast multinucleation and bone mass

Marie Pereira (1, 2) , Jeong-Hun Ko (1, 2) , John Logan (1, 2) , Hayley Protheroe (1, 2) , Kee-Beom Kim (3) , Amelia Li Min Tan (4) , Peter I Croucher (5) , Kwon-Sik Park (3) , Maxime Rotival (6) , Enrico Petretto (4) , Jh Duncan Bassett (1, 2) , Graham R Williams (1, 2) , Jacques Behmoaras (1, 2)

1 Imperial College London
2 Hammersmith Hospital NHS Imperial College Healthcare
3 University of Virginia
4 Duke-NUS Medical School [Singapore]
5 UNSW - University of New South Wales [Sydney]
6 Génétique Evolutive Humaine - Human Evolutionary Genetics

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.

Mots clés: Bone Biology; Cell biology and structure; Genetics Humans; Genomics and evolution; Human - human interaction; Network - organization; Osteoclast gene; Rat and human model

Domaines: Génétique humaine; Organisation et fonctions cellulaires [q-bio.SC]

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, 2020, 9, pp.e55549. ⟨10.7554/eLife.55549⟩. ⟨pasteur-03696673⟩