Genome-wide Analysis Of Histone H3 Lysine9 Modifications In Human Mesenchymal Stem Cell Osteogenic Differentiation

Mesenchymal stem cells (MSCs) of non-embryonic origins possess the self-renewal and multi-lineage differentiation potentials. It has been established that epigenetic mechanisms such as histone modifications could be critical for determining the fate of stem cells. In this study, full human genome promoter microarrays and expression microarrays were used to examine the roles of histone modifications (H3-Lys9 acetylation and dimethylation) in regulation of gene expression in human bone marrow MSCs and upon MSC osteogenic differentiation. We showed that modifications of histone H3-Lys9 at gene promoters correlated well with mRNA expression in human bone marrow MSCs. Functional analysis revealed that many key cellular pathways in human bone marrow MSC self-renewal, such as the canonical signaling pathways, cell cycle pathways and cytokine related pathways may be regulated by H3-Lys9 modifications. Our results also revealed that the enrichment of H3-Lys9 acetylation was decreased globally at the gene promoters, whereas the number of promoters enriched with H3-Lys9 dimethylation was increased evidently upon osteogenic induction. By combined analysis of data from both ChIP-on-chip and expression microarrays, a number of differentially expressed genes monitored by changes of H3-Lys9 acetylation and/or dimethylation were identified, implicating their roles in several biological events, such as cell cycle withdraw and cytoskeleton reconstruction that were essential to differentiation process. In addition, our results also showed that vitamin D receptor played a trans-repression role via alternations of H3K9Ac and H3K9Me2, upon MSC osteogenic differentiation. Our data suggest that gene activation and silencing affected by H3-Lys9 acetylation and dimethylation, respectively, may be essential to the maintenance of human bone marrow MSC self-renewal, multi-potency and differentiation process. This study provides information about genes that are important for MSC self-renewing and osteogenic differentiation, as well as the epigenetic mechanisms that regulate their expression.