A trans-eQTL network regulates osteoclast multinucleation and bone mass

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 ac...

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Main Authors: Marie Pereira, Jeong-Hun Ko, John Logan, Hayley Protheroe, Kee-Beom Kim, Amelia Li Min Tan, Peter I Croucher, Kwon-Sik Park, Maxime Rotival, Enrico Petretto, JH Duncan Bassett, Graham R Williams, Jacques Behmoaras
Format: Article
Language:English
Published: eLife Sciences Publications Ltd 2020-06-01
Series:eLife
Subjects:
mouse
rat
bone
osteoclast
network
Online Access:https://elifesciences.org/articles/55549
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spelling doaj-3598a6a41082456e82266d54eb35c4ad2021-05-05T21:13:27ZengeLife Sciences Publications LtdeLife2050-084X2020-06-01910.7554/eLife.55549A trans-eQTL network regulates osteoclast multinucleation and bone massMarie Pereira0https://orcid.org/0000-0003-0711-3385Jeong-Hun Ko1John Logan2Hayley Protheroe3Kee-Beom Kim4Amelia Li Min Tan5Peter I Croucher6Kwon-Sik Park7Maxime Rotival8Enrico Petretto9JH Duncan Bassett10https://orcid.org/0000-0003-0817-0082Graham R Williams11https://orcid.org/0000-0002-8555-8219Jacques Behmoaras12Centre for Inflammatory Disease, Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College London, London, United Kingdom; Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United KingdomCentre for Inflammatory Disease, Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College London, London, United Kingdom; Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United KingdomMolecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United KingdomMolecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United KingdomDepartment of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United StatesDuke-NUS Medical School, Singapore, SingaporeThe Garvan Institute of Medical Research and St. Vincent's Clinical School, University of NewSouth Wales Medicine, Sydney, AustraliaDepartment of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, United StatesHuman Evolutionary Genetics Unit, Institut Pasteur, Centre National de la Recherche Scientifique, UMR 2000, Paris, FranceDuke-NUS Medical School, Singapore, SingaporeMolecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United KingdomMolecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Hammersmith Hospital, Imperial College London, London, United KingdomCentre for Inflammatory Disease, Department of Immunology and Inflammation, Hammersmith Hospital, Imperial College London, London, United KingdomFunctional 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.https://elifesciences.org/articles/55549mouseratboneosteoclastnetwork
collection DOAJ
language English
format Article
sources DOAJ
author Marie Pereira
Jeong-Hun Ko
John Logan
Hayley Protheroe
Kee-Beom Kim
Amelia Li Min Tan
Peter I Croucher
Kwon-Sik Park
Maxime Rotival
Enrico Petretto
JH Duncan Bassett
Graham R Williams
Jacques Behmoaras
spellingShingle Marie Pereira
Jeong-Hun Ko
John Logan
Hayley Protheroe
Kee-Beom Kim
Amelia Li Min Tan
Peter I Croucher
Kwon-Sik Park
Maxime Rotival
Enrico Petretto
JH Duncan Bassett
Graham R Williams
Jacques Behmoaras
A trans-eQTL network regulates osteoclast multinucleation and bone mass
eLife
mouse
rat
bone
osteoclast
network
author_facet Marie Pereira
Jeong-Hun Ko
John Logan
Hayley Protheroe
Kee-Beom Kim
Amelia Li Min Tan
Peter I Croucher
Kwon-Sik Park
Maxime Rotival
Enrico Petretto
JH Duncan Bassett
Graham R Williams
Jacques Behmoaras
author_sort Marie Pereira
title A trans-eQTL network regulates osteoclast multinucleation and bone mass
title_short A trans-eQTL network regulates osteoclast multinucleation and bone mass
title_full A trans-eQTL network regulates osteoclast multinucleation and bone mass
title_fullStr A trans-eQTL network regulates osteoclast multinucleation and bone mass
title_full_unstemmed A trans-eQTL network regulates osteoclast multinucleation and bone mass
title_sort trans-eqtl network regulates osteoclast multinucleation and bone mass
publisher eLife Sciences Publications Ltd
series eLife
issn 2050-084X
publishDate 2020-06-01
description 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.
topic mouse
rat
bone
osteoclast
network
url https://elifesciences.org/articles/55549
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