A trans-eQTL network regulates osteoclast multinucleation and bone mass
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.
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Medical Research Council (MR/N01121X/1)
- J H Duncan Bassett
- Graham R Williams
- Jacques Behmoaras
- J H Duncan Bassett
- Graham R Williams
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All studies were performed in accordance to the U.K. Animal (Scientific Procedures) Act 1986, the ARRIVE guidelines, the EU Directive 2010/63/EU for animal experiments and practices prescribed by the National Institutes of Health in the United States.
- Charles Farber, University of Virginia, United States
- Received: January 28, 2020
- Accepted: June 12, 2020
- Accepted Manuscript published: June 19, 2020 (version 1)
- Version of Record published: July 10, 2020 (version 2)
© 2020, Pereira et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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