Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells

Figure 9

Model for BIX01294 and TSA mediated induction of MSC cardiocompetency. (a) G9a HMTase and HDAC activity in MSCs maintains precardiac genes in a closed chromatin configuration and thus are transcriptionally silent. BIX01294 treatment inhibits G9a HMTase methylation of histone H3 lysine residues H3K9 and H3K27 within genes associated with precardiac progenitors, such as Mesp1 and brachyury, thus allowing these genes to be expressed and conferring MSCs with a precardiac cell potential. (b) While inhibition of HDACs by TSA is not sufficient to promote Mesp1 or brachyury expression from bone marrow MSCs, this drug acts synergistically (asterisk) with BIX01294 in the transcriptional activation of precardiac gene expression and acquisition of a cardiac competent cell phenotype. We hypothesize that this enhanced precardiac gene expression and cardiocompetency supported by the coaddition of these two drugs is due to their cooperative enhancement of H3K27 acetylation (asterisks), which is a known epigenetic indicator of cardiac gene expression in the early embryo.

(a)

(b)