Methylome analysis of human bone marrow MSCs reveals extensive age- and culture-induced changes at distal regulatory elements
Pasumarthy, Kalyan K.; Jayavelu, Naresh Doni; Kilpinen, Lotta; Andrus, Colin; Battle, Stephanie L.; Korhonen, Matti; Lehenkari, Petri; Lund, Riikka; Laitinen, Saara; Hawkins, R. David (2017-08-24)
Pasumarthy, K., Doni Jayavelu, N., Kilpinen, L., Andrus, C., Battle, S., Korhonen, M., Lehenkari, P., Lund, R., Laitinen, S., Hawkins, R. (2017) Methylome Analysis of Human Bone Marrow MSCs Reveals Extensive Age- and Culture-Induced Changes at Distal Regulatory Elements. Stem Cell Reports, 9 (3), 999-1015. doi:10.1016/j.stemcr.2017.07.018
© 2017 The authors. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Human bone marrow stromal cells, or mesenchymal stem cells (BM-MSCs), need expansion prior to use as cell-based therapies in immunological and tissue repair applications. Aging and expansion of BM-MSCs induce epigenetic changes that can impact therapeutic outcomes. By applying sequencing-based methods, we reveal that the breadth of DNA methylation dynamics associated with aging and expansion is greater than previously reported. Methylation changes are enriched at known distal transcription factor binding sites such as enhancer elements, instead of CpG-rich regions, and are associated with changes in gene expression. From this, we constructed hypo- and hypermethylation-specific regulatory networks, including a sub-network of BM-MSC master regulators and their predicted target genes, and identified putatively disrupted signaling pathways. Our genome-wide analyses provide a broader overview of age- and expansion-induced DNA methylation changes and a better understanding of the extent to which these changes alter gene expression and functionality of human BM-MSCs.
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