A trans-eQTL network regulates osteoclast multinucleation and bone mass.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 32553114.
- Also identified by DOI 10.7554/eLife.55549 and PMC identifier 7351491.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>trans</i>-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 <i>Bcat1</i> and seven other co-regulated MMnet genes out of 13, regulate bone function. Specifically, global (<i>Pik3cb<sup>-/-</sup></i>, <i>Atp8b2<sup>+/-</sup></i>, <i>Igsf8<sup>-/-</sup></i>, <i>Eml1<sup>-/-</sup></i>, <i>Appl2<sup>-/-</sup></i>, <i>Deptor<sup>-/-</sup></i>) and myeloid-specific <i>Slc40a1</i> 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.
Medical subject headings
- Bone Density
- Bone Resorption
- Gene Regulatory Networks
- Genome-Wide Association Study
- Osteoclasts
- Quantitative Trait Loci