Systems genetic analysis of osteoblast-lineage cells

Gina Calabrese, Brian J Bennett, Luz Orozco, Hyun M Kang, Eleazar Eskin, Carlos Dombret, Olivier De Backer, Aldons J Lusis, Charles R Farber

Research output: Contribution to journalArticle

Abstract

The osteoblast-lineage consists of cells at various stages of maturation that are essential for skeletal development, growth, and maintenance. Over the past decade, many of the signaling cascades that regulate this lineage have been elucidated; however, little is known of the networks that coordinate, modulate, and transmit these signals. Here, we identify a gene network specific to the osteoblast-lineage through the reconstruction of a bone co-expression network using microarray profiles collected on 96 Hybrid Mouse Diversity Panel (HMDP) inbred strains. Of the 21 modules that comprised the bone network, module 9 (M9) contained genes that were highly correlated with prototypical osteoblast maker genes and were more highly expressed in osteoblasts relative to other bone cells. In addition, the M9 contained many of the key genes that define the osteoblast-lineage, which together suggested that it was specific to this lineage. To use the M9 to identify novel osteoblast genes and highlight its biological relevance, we knocked-down the expression of its two most connected "hub" genes, Maged1 and Pard6g. Their perturbation altered both osteoblast proliferation and differentiation. Furthermore, we demonstrated the mice deficient in Maged1 had decreased bone mineral density (BMD). It was also discovered that a local expression quantitative trait locus (eQTL) regulating the Wnt signaling antagonist Sfrp1 was a key driver of the M9. We also show that the M9 is associated with BMD in the HMDP and is enriched for genes implicated in the regulation of human BMD through genome-wide association studies. In conclusion, we have identified a physiologically relevant gene network and used it to discover novel genes and regulatory mechanisms involved in the function of osteoblast-lineage cells. Our results highlight the power of harnessing natural genetic variation to generate co-expression networks that can be used to gain insight into the function of specific cell-types.
Original languageEnglish
Pages (from-to)e1003150
JournalPLoS Genetics
Volume8
Issue number12
DOIs
Publication statusPublished - 2012

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osteoblasts
genetic analysis
Osteoblasts
genetic techniques and protocols
gene
bone
bone density
cells
Bone Density
genes
Genes
Gene Regulatory Networks
bones
Bone and Bones
mice
mineral
skeletal development
Quantitative Trait Loci
Genome-Wide Association Study
Regulator Genes

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Calabrese, G., Bennett, B. J., Orozco, L., Kang, H. M., Eskin, E., Dombret, C., ... Farber, C. R. (2012). Systems genetic analysis of osteoblast-lineage cells. PLoS Genetics, 8(12), e1003150. https://doi.org/10.1371/journal.pgen.1003150
Calabrese, Gina ; Bennett, Brian J ; Orozco, Luz ; Kang, Hyun M ; Eskin, Eleazar ; Dombret, Carlos ; De Backer, Olivier ; Lusis, Aldons J ; Farber, Charles R. / Systems genetic analysis of osteoblast-lineage cells. In: PLoS Genetics. 2012 ; Vol. 8, No. 12. pp. e1003150.
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Calabrese, G, Bennett, BJ, Orozco, L, Kang, HM, Eskin, E, Dombret, C, De Backer, O, Lusis, AJ & Farber, CR 2012, 'Systems genetic analysis of osteoblast-lineage cells', PLoS Genetics, vol. 8, no. 12, pp. e1003150. https://doi.org/10.1371/journal.pgen.1003150

Systems genetic analysis of osteoblast-lineage cells. / Calabrese, Gina; Bennett, Brian J; Orozco, Luz; Kang, Hyun M; Eskin, Eleazar; Dombret, Carlos; De Backer, Olivier; Lusis, Aldons J; Farber, Charles R.

In: PLoS Genetics, Vol. 8, No. 12, 2012, p. e1003150.

Research output: Contribution to journalArticle

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AU - Calabrese, Gina

AU - Bennett, Brian J

AU - Orozco, Luz

AU - Kang, Hyun M

AU - Eskin, Eleazar

AU - Dombret, Carlos

AU - De Backer, Olivier

AU - Lusis, Aldons J

AU - Farber, Charles R

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Calabrese G, Bennett BJ, Orozco L, Kang HM, Eskin E, Dombret C et al. Systems genetic analysis of osteoblast-lineage cells. PLoS Genetics. 2012;8(12):e1003150. https://doi.org/10.1371/journal.pgen.1003150