Epigenetic Regulators of Mesenchymal Stem/Stromal Cell Lineage Determination

Abstract

Purpose of Review Although many signalling pathways have been discovered to be essential in mesenchymal stem/stromal (MSC) differentiation, it has become increasingly clear in recent years that epigenetic regulation of gene transcription is a vital component of lineage determination, encompassing diet, lifestyle and parental influences on bone, fat and cartilage development. Recent Findings This review discusses how specific enzymes that modify histone methylation and acetylation or DNA methylation orchestrate the differentiation programs in lineage determination of MSC and the epigenetic changes that facilitate development of bone related diseases such as osteoporosis. The review also describes how environmental factors such as mechanical loading influence the epigenetic signatures of MSC, and how the use of chemical agents or small peptides can regulate epigenetic drift in MSC populations during ageing and disease. Summary Epigenetic regulation of MSC lineage commitment is controlled through changes in enzyme activity, which modifies DNA and histone residues leading to alterations in chromatin structure. The co-ordinated epigenetic regulation of transcriptional activation and repression act to mediate skeletal tissue homeostasis, where deregulation of this process can lead to bone loss during ageing or osteoporosis.

Epigenetic Control of Osteogenic Lineage Commitment

“…Runx2 binds to and activates the Sp7 promoter ( Yoshida et al, 2012 ), indicating that Runx2 is an upstream transcription factor during osteogenesis, but that this differentiation process requires the expression of both master regulators ( Long, 2012 ). In recent years, several groups have demonstrated that changes in chromatin structure and expression of the Runx2 and Sp7 genes are epigenetically-controlled ( Yang et al, 2013 , 2015 ; Tai et al, 2014 ; Dudakovic et al, 2015 ; Rojas et al, 2015 , 2019 ; Zhang et al, 2015 ; Aguilar et al, 2016 , 2020 ; Park-Min, 2016 ; Zhou et al, 2016 ; Sepulveda et al, 2017a ; Cakouros and Gronthos, 2020 ; Figure 1 ).…”

“…Findings from several teams revealed that regulating the repressive mark H3K27me3 represents an important step during the differentiation of MSCs toward osteoblasts. It was demonstrated that the activity of the H3K27 demethylases Utx/Kdm6a and Jmjd3/Kdm6b is critical for erasing this mark from the promoter of the Runx2 and Sp7 genes ( Figure 1 ) and hence to induce their expression during osteogenesis ( Ye et al, 2012 ; Hemming et al, 2014 ; Rojas et al, 2015 ; Park-Min, 2016 ; Sepulveda et al, 2017b ; Cakouros and Gronthos, 2020 ; Sen et al, 2020 ). Additionally, an increased activity of the PRC2 complex that “writes” the H3K27me3 mark, can significantly limit the ability of MSCs to engage osteogenic differentiation ( Wei et al, 2010 ).…”

MicroRNAs Modulate Signaling Pathways in Osteogenic Differentiation of Mesenchymal Stem Cells

“…Growing evidence shows that MSC differentiation is influenced by several epigenetic processes/factors, including histone methylation and acetylation, DNA methylation [ 23 ], non-coding RNA molecules, such as long non-coding RNAs (lncRNA) [ 24 ], and miRNAs [ 25 , 26 , 27 , 28 ].…”

Epigenetics of Aging and Aging-Associated Diseases

“…Osteoporosis is tightly linked to aging via epigenetic changes in mesenchymal stem cells (MSCs) [ 163 ]. Physiologically, the Osterix promoter was shown to entail enriched levels of H3Ac/H3K4me3 and reduced levels of H3K9me3/H3K27me3, inducing the differentiation of MSCs into osteoblasts to mediate skeletal tissue homeostasis [ 163 , 164 ]. Among the key transcription factors for osteogenesis are HOX and RUNX2, both of which are hypermethylated in aged MSCs [ 165 ].…”

“…It was shown in human bone marrow stromal cells (BMSCs) that in osteoporosis the number of clonogenic BMSCs was reduced, corresponding to decreased levels of Tet1 and Tet2 , factors, which are able to erase DNA methylation. During normal osteogenesis, TET1 and TET2 levels were enhanced with an increased binding to the Osterix promoter [ 163 , 167 ]. Yang et al detected an osteopenic phenotype and decreased Runx2 expression in Tet1 −/− Prx1 cre Tet2 fl/fl mice.…”