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. 2016 Apr 7;20(8):1589–1602. doi: 10.1111/jcmm.12845

Figure 3.

Figure 3

Potential epigenetic actions of IGF‐I in the developing heart muscle. When histone 3 (H3) is tri‐methylated (me3) at lysine 27 (K27) residue, it is associated with inactive gene promoters. Because of its dramatic and predictable effect on gene expression, H3K27me3 is a great marker for epigenetically inactivated genes. EZH2 catalyzes di‐ and tri‐methylation of the K27 residue of histone H3 (H3K27me2/3). High expression of EZH2 in stem cells is associated with modified nucleosomes at the promoters of important developmental transcription factors such as OCT4, thus preventing premature activation of the lineage‐committing markers 158, 159. Growth factors such as IGFs activate AKT that in turn phosphorylates EZH2 at Ser21 residue blocking its methy‐transferase activity and consequently de‐repressing gene‐promoters. (1) Based on the above principles, here we hypothesize that IGF‐I and/or vascular endothelial factor (VEGF) can activate AKT which in turn induces pEZH2Ser‐21 suppressing its methyltransferase activity and the binding of histone H3 at the OCT4 promoter 79 in cardiac stem cells. (2) It is known that EZH2 and NFkB crosstalk in cancer mechanisms 84 where EZH2 functions as a multitasking molecule that can either act as a transcriptional activator or a repressor of the NF‐κB targets 84. This will depend on the cellular micro‐environment and perhaps on IGF‐I that may be a key‐factor. In fact, IGF‐I can signal either through AKT or through the IGFIR/PI3K/Raptor/mTOR loop and in both cases it is possible that it may de‐repress the NFkB promoter through EZH2 157. Ablation of NFkB activity with a specific inhibitor (BAY) impairs vasculogenesis in the neonatal lung and in the same tissue chromatin immuno‐precipitation reactions showed that NFkB binds directly the promoter of the VEGF‐2 59. Here we hypothesize that either VEGF or IGF‐I signalling through AKT, activates mTOR which in turn may lead EZH2 polycomb protein to de‐repressing the NFkB promoter, making possible the remodeling of the endothelial tissue in the heart.