Differential DNA Methylation Encodes Proliferation and Senescence Programs in Human Adipose-Derived Mesenchymal Stem Cells

• Published in: Frontiers in genetics Vol. 11; p. 346
• Main Authors: Pepin, Mark E., Infante, Teresa, Benincasa, Giuditta, Schiano, Concetta, Miceli, Marco, Ceccarelli, Simona, Megiorni, Francesca, Anastasiadou, Eleni, Della Valle, Giovanni, Fatone, Gerardo, Faenza, Mario, Docimo, Ludovico, Nicoletti, Giovanni F., Marchese, Cinzia, Wende, Adam R., Napoli, Claudio
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 15.04.2020
• Subjects: 5′-azacitidine; computational biology; epigenomics and epigenetics; Genetics; regenerative medicine; stem cell biology; Whole-genome DNA methylation; computational biology; 5′-azacitidine; Whole-genome DNA methylation; stem cell biology; regenerative medicine; cellular reprogramming; epigenomics and epigenetics
• ISSN: 1664-8021; 1664-8021
• DOI: 10.3389/fgene.2020.00346

Adult adipose tissue-derived mesenchymal stem cells (ASCs) constitute a vital population of multipotent cells capable of differentiating into numerous end-organ phenotypes. However, scientific and translational endeavors to harness the regenerative potential of ASCs are currently limited by an incomplete understanding of the mechanisms that determine cell-lineage commitment and stemness. In the current study, we used reduced representation bisulfite sequencing (RRBS) analysis to identify epigenetic gene targets and cellular processes that are responsive to 5'-azacitidine (5'-AZA). We describe specific changes to DNA methylation of ASCs, uncovering pathways likely associated with the enhancement of their proliferative capacity. We identified 4,797 differentially methylated regions (FDR < 0.05) associated with 3,625 genes, of which 1,584 DMRs annotated to the promoter region. Gene set enrichment of differentially methylated promoters identified "phagocytosis," "type 2 diabetes," and "metabolic pathways" as disproportionately hypomethylated, whereas "adipocyte differentiation" was the most-enriched pathway among hyper-methylated gene promoters. Weighted coexpression network analysis of DMRs identified clusters associated with cellular proliferation and other developmental programs. Furthermore, the ELK4 binding site was disproportionately hyper-methylated within the promoters of genes associated with AKT signaling. Overall, this study offers numerous preliminary insights into the epigenetic landscape that influences the regenerative capacity of human ASCs.