RT Journal Article
SR Electronic
T1 A trans-eQTL network regulates osteoclast multinucleation and bone mass
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.02.13.947705
DO 10.1101/2020.02.13.947705
A1 Marie Pereira
A1 Jeong-Hun Ko
A1 John Logan
A1 Hayley Protheroe
A1 Kee-Beom Kim
A1 Amelia Li Min Tan
A1 Kwon-Sik Park
A1 Maxime Rotival
A1 Enrico Petretto
A1 J. H. Duncan Bassett
A1 Graham R. Williams
A1 Jacques Behmoaras
YR 2020
UL http://biorxiv.org/content/early/2020/02/13/2020.02.13.947705.abstract
AB 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 Slc40a1ΔLysMCre 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 statement We 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.