Imprinting defects at human 14q32 locus alters gene expression and is associated with the pathobiology of osteosarcoma.

Jingmin Shu,Subbaya Subramanian,Emily A Pope,Logan Spector,Jyotika Varshney,David A Largaespada,Anne E Sarver,Lihua Li,Venugopal Thayanithy,Clifford J Steer

doi:10.18632/oncotarget.6965

Jingmin Shu, Subbaya Subramanian + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.6965

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Journal: Oncotarget	Publication Date: Jan 21, 2016
Citations: 18	License type: cc-by

Affiliation: Cancer Research Center, University of Minnesota

Abstract

Osteosarcoma is the most common primary bone malignancy affecting children and adolescents. Although several genetic predisposing conditions have been associated with osteosarcoma, our understanding of its pathobiology is rather limited. Here we show that, first, an imprinting defect at human 14q32-locus is highly prevalent (87%) and specifically associated with osteosarcoma patients < 30 years of age. Second, the average demethylation at differentially methylated regions (DMRs) in the 14q32-locus varied significantly compared to genome-wide demethylation. Third, the 14q32-locus was enriched in both H3K4-me3 and H3K27-me3 histone modifications that affected expression of all imprinted genes and miRNAs in this region. Fourth, imprinting defects at 14q32 - DMRs are present in triad DNA samples from affected children and their biological parents. Finally, imprinting defects at 14q32-DMRs were also observed at higher frequencies in an Rb1/Trp53 mutation-induced osteosarcoma mouse model. Further analysis of normal and tumor tissues from a Sleeping Beauty mouse model of spontaneous osteosarcoma supported the notion that these imprinting defects may be a key factor in osteosarcoma pathobiology. In conclusion, we demonstrate that imprinting defects at the 14q32 locus significantly alter gene expression, may contribute to the pathogenesis of osteosarcoma, and could be predictive of survival outcomes.

Highlights

Osteosarcoma is an aggressive bone cancer predominantly affecting children and young adolescents with a 5-year survival rate of ~70% [1]
The results of our study suggest that hypomethylation at 14q32 - imprinted IG-differentially methylated regions (DMRs) is predominantly associated with osteosarcoma and is a likely mechanism of downregulation of imprinted genes and miRNAs at this locus
Hypomethylation typically leads to increased gene expression, it has been reported that hierarchical interaction of the methylation pattern in the three DMRs at the 14q32 locus does have a negative effect on gene expression [36, 37]

Summary

Introduction

Osteosarcoma is an aggressive bone cancer predominantly affecting children and young adolescents with a 5-year survival rate of ~70% [1]. The 14q32 imprinted region is ∼1 Mb in size and contains both paternally (DLK1, RTL1 and DIO3) and maternally (MEG3, MEG8 and DIO3OS) expressed genes [12, 13] These imprinted genes have key roles in cellular functions [14,15,16], bone differentiation [17, 18], and can serve as markers for complete reprogramming of induced pluripotent stem (iPS) cells [19]. This imprinted locus includes over 40 miRNAs, a subset of which cooperatively regulates cMYC expression in osteosarcoma [11]. It is likely that dysregulated expression of genes and miRNAs resulting from disordered imprinting at this locus could contribute to the pathogenesis of osteosarcoma [20, 21]

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