Abstract
Mesenchymal stem cells (MSCs) specifically differentiate into cardiomyocytes as a potential way to reverse myocardial injury diseases, and uncovering this differentiation mechanism is immensely important. We have previously shown that histone acetylation/methylation and DNA methylation are involved in MSC differentiation into cardiomyocytes induced by islet-1. These modifications regulate cardiac-specific genes by interacting with each other in the promoter regions of these genes, but the molecular mechanism of these interactions remains unknown. In this study, we found that the key enzymes that regulate GATA4/Nkx2.5 expression are Gcn5/HDAC1, G9A, and DNMT-1. When α-methylene-γ-butyrolactone 3 (MB-3) was used to inhibit Gcn5 expression, we observed that the interactions among these key enzymes in the GATA4/Nkx2.5 promoters were blocked, and MSCs could not be induced into cardiomyocytes. Our results indicated that islet-1 could induce Gcn5 binding to GATA4/Nkx2.5 promoter regions and induce the interactions among Gcn5, HDAC1, G9A and DNMT-1, which upregulated GATA4/Nkx2.5 expression and promoted MSC differentiation into cardiomyocytes.
Highlights
Mesenchymal stem cells (MSCs) differentiate into cardiomyocytes as a potential way to reverse myocardial injury diseases, and uncovering this differentiation mechanism is immensely important
We investigated the molecular mechanism and found that histone modifications and DNA methylation are very important for MSC differentiation; these epigenetic modifications interact with each other during MSC differentiation into cardiomyocytes[11,12]
The binding level of Suv39h1 did not obviously change during the period of differentiation (Fig. 3d). These results suggest that G9A is the key HMT involved in regulating the histone methylation level in the GATA4/Nkx2.5 promoter region during MSC differentiation into cardiomyocytes
Summary
Mesenchymal stem cells (MSCs) differentiate into cardiomyocytes as a potential way to reverse myocardial injury diseases, and uncovering this differentiation mechanism is immensely important. We have previously shown that histone acetylation/methylation and DNA methylation are involved in MSC differentiation into cardiomyocytes induced by islet-1 These modifications regulate cardiac-specific genes by interacting with each other in the promoter regions of these genes, but the molecular mechanism of these interactions remains unknown. DNMT-1 is involved in the maintenance of methylation, and DNMT3a/b functions as a de novo methyltransferase[18,19] It remains unclear which specific enzymes are involved in islet-1-induced MSC differentiation into cardiomyocytes and how these enzymes interact with each other. We further investigated the specific enzyme that is involved in regulating GATA4 and Nkx2.5 and the molecular mechanism of the epigenetic interaction of these two cardiac-specific transcript factor promoter regions.
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