Fig. 3: Epigenetic changes during osteogenic differentiation.

Osteogenesis is a three-step process consisting of the proliferative phase, matrix maturation, and mineralization. The process is controlled by RUNX2 and OSX transcription factors. In MSCs, their expression is inhibited by repressive marks, namely histone H3 mono-methylation at the 4^th lysine residue (H3K4me1), histone H3 tri-methylation at the 9^th lysine residue (H3K9me3), histone H3 tri-methylation of 27^th lysine residue (H3K27me3), and DNA methylation at the 5^th carbon of cytosine (5mCpG). After induction of differentiation, expression of methyltransferases (KMT2C and KMT2D) is reduced, and repressive marks are removed by SWItch/Sucrose non-fermentable complex (SWI/SNF) and histone demethylases (KDM4B and KDM6B) activity. They are replaced by activation marks, namely histone H3 tri-methylation at the 4^th lysine residue (H3K4me3) and acetylation (ac) of histones H3 and H4, which opened the chromatin for RUNX2 and OSX expression. Histone acetylation is mediated by p300HAT (p300 histone acetyltransferase) and accompanied by decreased expression of HDAC1-3 (Histone deacetylases 1-3), while H3K4me3 is mediated by SET1/COMPASS and KMT2B activity and accompanied by reduced expression of KDM5B. Created with BioRender.com.