A trans-eqtl network regulates osteoclast multinucleation and bone mass

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

doi:10.7554/eLife.55549

A trans-eqtl network regulates osteoclast multinucleation and bone mass

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

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22 Scopus citations

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 transregulated 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 myeloidspecific 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.

Original language	English
Article number	e55549
Pages (from-to)	1-21
Number of pages	21
Journal	eLife
Volume	9
DOIs	https://doi.org/10.7554/eLife.55549
State	Published - Jun 2020

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title = "A trans-eqtl network regulates osteoclast multinucleation and bone mass",

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 transregulated 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 myeloidspecific 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.",

author = "Marie Pereira and Ko, {Jeong Hun} and John Logan and Hayley Protheroe and Kim, {Kee Beom} and Tan, {Amelia Li Min} and Croucher, {Peter I.} and Park, {Kwon Sik} and Maxime Rotival and Enrico Petretto and Bassett, {JH Duncan} and Williams, {Graham R.} and Jacques Behmoaras",

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year = "2020",

month = jun,

doi = "10.7554/eLife.55549",

language = "English",

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AU - Pereira, Marie

AU - Ko, Jeong Hun

AU - Logan, John

AU - Protheroe, Hayley

AU - Kim, Kee Beom

AU - Tan, Amelia Li Min

AU - Croucher, Peter I.

AU - Park, Kwon Sik

AU - Rotival, Maxime

AU - Petretto, Enrico

AU - Bassett, JH Duncan

AU - Williams, Graham R.

AU - Behmoaras, Jacques

PY - 2020/6

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N2 - 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 transregulated 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 myeloidspecific 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.

AB - 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 transregulated 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 myeloidspecific 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.

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A trans-eqtl network regulates osteoclast multinucleation and bone mass

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