Abstract
BackgroundAutosomal dominant osteopetrosis type II (ADO2) is a genetically and phenotypically metabolic bone disease, caused by osteoclast abnormalities. The pathways dysregulated in ADO2 could lead to the defects in osteoclast formation and function. However, the mechanism remains elusive.Materials and methodsTo systematically explore the molecular characterization of ADO2, we performed a multi-omics profiling from the autosomal dominant osteopetrosis type II iPSCs (ADO2-iPSCs) and healthy normal control iPSCs (NC-iPSCs) using whole genome re-sequencing, DNA methylation and N6-methyladenosine (m6A) analysis in this study.ResultsTotally, we detected 7,095,817 single nucleotide polymorphisms (SNPs) and 1,179,573 insertion and deletions (InDels), 1,001,943 differentially methylated regions (DMRs) and 2984 differential m6A peaks, and the comprehensive multi-omics profile was generated from the two cells. Interestingly, the ISG15 m6A level in ADO2-iPSCs is higher than NC-iPSCs by IGV software, and the differentially expressed m6A-modified genes (DEMGs) were highly enriched in the osteoclast differentiation and p53 signaling pathway, which associated with the development of osteopetrosis. In addition, combining our previously published transcriptome and proteome datasets, we found that the change in DNA methylation levels correlates inversely with some gene expression levels.ConclusionOur results indicate that the global multi-omics landscape not only provides a high-quality data resource but also reveals a dynamic pattern of gene expression, and found that the pathogenesis of ADO2 may begin early in life.
Highlights
Autosomal dominant osteopetrosis type II (ADO2) is a rare human inherited metabolic bone disease characterized by increased bone brittleness, mass and density due to osteoclast abnormalities [1,2,3]
Totally, we detected 7,095,817 single nucleotide polymorphisms (SNPs) and 1,179,573 insertion and deletions (InDels), 1,001,943 differentially methylated regions (DMRs) and 2984 differential m6A peaks, and the comprehensive multi-omics profile was generated from the two cells
The ISG15 m6A level in Autosomal dominant osteopetrosis type 2 (ADO2)-iPSCs is higher than NC-iPSCs by IGV software, and the differentially expressed m6A-modified genes (DEMGs) were highly enriched in the osteoclast differentiation and p53 signaling pathway, which associated with the development of osteopetrosis
Summary
Autosomal dominant osteopetrosis type II (ADO2) is a rare human inherited metabolic bone disease characterized by increased bone brittleness, mass and density due to osteoclast abnormalities [1,2,3]. Large-scale whole exome-sequenced studies of osteopetrosis have revealed more than 50 heterozygous mutations in the CLCN7 gene, which can lead to ADO2, among which the p.G215R has been studied extensively [13,14,15] Ou and his colleagues have been identified a great number of miRNAs and proteins in the peripheral blood mononuclear cells from patients with osteopetrosis, and found that the changes in miRNA expression profiles suggest epigenetic variation [12].
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