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

Research output: Contribution to journal › Article › peer-review

23 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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10.7554/eLife.55549

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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",

note = "Publisher Copyright: {\textcopyright} Pereira et al.",

year = "2020",

month = jun,

doi = "10.7554/eLife.55549",

language = "English",

volume = "9",

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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

Y1 - 2020/6

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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VL - 9

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JO - eLife

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ER -

A trans-eqtl network regulates osteoclast multinucleation and bone mass

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