Abstract
Bone marrow mesenchymal stem cells (BMSCs) nowadays are regarded as promising candidates in cell-based therapy for the regeneration of damaged bone tissues that are either incurable or intractable due to the insufficiency of current therapies. Recent studies suggest that BMSCs differentiate into osteoblasts, and that this differentiation is regulated by some specific patterns of epigenetic modifications, such as DNA methylation. However, the potential role of DNA methylation modification in BMSC osteogenic differentiation is unclear. In this study, we performed a genome-wide study of DNA methylation between the noninduced and induced osteogenic differentiation of BMSCs at day 7. We found that the majority of cytosines in a CpG context were methylated in induced BMSCs. Our results also revealed that, along with the induced osteogenic differentiation in BMSCs, the average genomic methylation levels and CpG methylation in transcriptional factor regions (TFs) were increased, the CpG methylation level of various genomic elements was mainly in the medium-high methylation section, and CpG methylation levels in the repeat element had highly methylated levels. The GO analysis of differentially methylated region- (DMR-) associated genes (DMGs) showed that GO terms, including cytoskeletal protein binding (included in Molecular Function GO terms), skeletal development (included in Biological Process GO terms), mesenchymal cell differentiation (included in Biological Process GO terms), and stem cell differentiation (included in Biological Process), were enriched in the hypermethylated DMGs. Then, the KEGG analysis results showed that the WNT pathway, inositol phosphate metabolism pathway, and cocaine addiction pathway were more correlative with the DMRs during the induced osteogenic differentiation in BMSCs. In conclusion, this study revealed the difference of methylated levels during the noninduced and induced osteogenic differentiation of BMSCs and provided useful information for future works to characterize the important function of epigenetic mechanisms on BMSCs' differentiation.
Highlights
Bone is a tissue most commonly damaged by aging or disease, and it has a limited ability for self-repair
It is reported that specific and reproducible epigenetic changes were acquired by mesenchymal stem cells (MSCs) during ex vivo culture, and DNA methylation patterns had highly significant differences only at specific CpG islands associated with promoter regions, such as in homeobox genes and genes involved in cell differentiation [22, 23]
It was shown that the average genomic methylation levels and CpG methylation in transcriptional factor regions were increased along with the osteogenic differentiation process in Bone marrow mesenchymal stem cells (BMSCs)
Summary
Bone is a tissue most commonly damaged by aging or disease, and it has a limited ability for self-repair. Cell-based therapy is considered as a prospective candidate for the regeneration of damaged bone tissues [5]. In light of their relative ease of isolation, low immune rejection, selfrenewing ability, and high multidifferentiation potential, mesenchymal stem cells (MSCs) are deemed as hopeful candidates for cell-based therapy [6,7,8]. Studies suggest that MSC homeostasis between self-renewal and differentiation is regulated by some specific patterns of epigenetic modifications, including DNA methylation [9, 10].
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