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Systems Genetic Analysis of Osteoblast-Lineage Cells
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نویسنده
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calabrese g. ,bennett b.j. ,orozco l. ,kang h.m. ,eskin e. ,dombret c. ,de backer o. ,lusis a.j. ,farber c.r.
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منبع
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plos genetics - 2012 - دوره : 8 - شماره : 12
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چکیده
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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. © 2012 calabrese et al.
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آدرس
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center for public health genomics,university of virginia,charlottesville,va, United States, department of genetics,university of north carolina at chapel hill,chapel hill,nc, United States, department of medicine,david geffen school of medicine,university of california los angeles,los angeles,ca, United States, department of biostatistics,university of michigan,ann arbor,mi, United States, department of computer science,university of california los angeles,los angeles,ca, United States, unité de recherche en physiologie moléculaire (urphym),namur research institute for life sciences (narilis),fundp school of medicine,university of namur,namur, Belgium, unité de recherche en physiologie moléculaire (urphym),namur research institute for life sciences (narilis),fundp school of medicine,university of namur,namur, Belgium, department of medicine,david geffen school of medicine,university of california los angeles,los angeles,ca,united states,department of human genetics,david geffen school of medicine,university of california los angeles,los angeles,ca,united states,department of microbiology,immunology,and molecular genetics,university of california los angeles,los angeles,ca, United States, center for public health genomics,university of virginia,charlottesville,va,united states,department of medicine,division of cardiovascular medicine,university of virginia,charlottesville,va,united states,department of biochemistry and molecular genetics,university of virginia,charlottesville,va, United States
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Authors
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