A trans-eQTL network regulates osteoclast multinucleation and bone mass
- Imperial College London, United Kingdom
- University of Virginia School of Medicine, United States
- Duke-NUS Medical School, Singapore
- Institut Pasteur, Centre National de la Recherche Scientifique, UMR 2000, France
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
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Author details
Funding
Medical Research Council (MR/N01121X/1)
- J H Duncan Bassett
- Graham R Williams
- Jacques Behmoaras
Wellcome (101123)
- 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.
Ethics
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.
Copyright
© 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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A trans-eQTL network regulates osteoclast multinucleation and bone mass
eLife 9:e55549.
https://doi.org/10.7554/eLife.55549
