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A trans-eQTL network regulates osteoclast multinucleation and bone mass

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Title: A trans-eQTL network regulates osteoclast multinucleation and bone mass
Authors: Pereira, M
Ko, J-H
Logan, J
Protheroe, H
Kim, K-B
Tan, ALM
Croucher, PI
Park, K-S
Rotival, M
Petretto, E
Bassett, JD
Williams, GR
Behmoaras, J
Item Type: Journal Article
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.
Issue Date: 10-Jul-2020
Date of Acceptance: 12-Jun-2020
URI: http://hdl.handle.net/10044/1/80983
DOI: 10.7554/eLife.55549
ISSN: 2050-084X
Publisher: eLife Sciences Publications Ltd
Journal / Book Title: eLife
Volume: 9
Issue: 7
Copyright Statement: © Copyright Pereira et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited. (https://creativecommons.org/licenses/by/4.0/)
Sponsor/Funder: Medical Research Council (MRC)
Medical Research Council (MRC)
Funder's Grant Number: MR/M004716/1
MR/N01121X/1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biology
Life Sciences & Biomedicine - Other Topics
GENOME-WIDE ASSOCIATION
MINERAL DENSITY
PHOSPHATIDYLINOSITOL 3-KINASE
SYSTEMS GENETICS
COMPLEX TRAITS
DC-STAMP
METAANALYSIS
RISK
DETERMINANTS
MACROPHAGES
bone
cell biology
genetics
genomics
human
mouse
network
osteoclast
rat
Animals
Bone Density
Bone Resorption
Female
Gene Regulatory Networks
Genome-Wide Association Study
Male
Mice
Mice, Knockout
Osteoclasts
Quantitative Trait Loci
Rats
Rats, Inbred Lew
Rats, Inbred WKY
Osteoclasts
Animals
Rats, Inbred Lew
Rats, Inbred WKY
Mice, Knockout
Mice
Rats
Bone Resorption
Bone Density
Quantitative Trait Loci
Female
Male
Gene Regulatory Networks
Genome-Wide Association Study
0601 Biochemistry and Cell Biology
Publication Status: Published
Article Number: ARTN e55549
Online Publication Date: 2020-06-19
Appears in Collections:Department of Immunology and Inflammation
Department of Metabolism, Digestion and Reproduction
Institute of Clinical Sciences
Faculty of Medicine



This item is licensed under a Creative Commons License Creative Commons