Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells
Previously, we reported that treatment with the G9a histone methyltransferase inhibitor BIX01294 causes bone marrow mesenchymal stem cells (MSCs) to exhibit a cardiocompetent phenotype, as indicated by the induction of the precardiac markers Mesp1 and brachyury. Here, we report that combining the hi...
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| Format: | Article |
| Language: | English |
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Wiley
2017-01-01
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| Series: | Stem Cells International |
| Online Access: | http://dx.doi.org/10.1155/2017/3464953 |
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| author | Jinpu Yang Keerat Kaur John G. Edwards Carol A. Eisenberg Leonard M. Eisenberg |
| author_facet | Jinpu Yang Keerat Kaur John G. Edwards Carol A. Eisenberg Leonard M. Eisenberg |
| author_sort | Jinpu Yang |
| collection | DOAJ |
| description | Previously, we reported that treatment with the G9a histone methyltransferase inhibitor BIX01294 causes bone marrow mesenchymal stem cells (MSCs) to exhibit a cardiocompetent phenotype, as indicated by the induction of the precardiac markers Mesp1 and brachyury. Here, we report that combining the histone deacetylase inhibitor trichostatin A (TSA) with BIX01294 synergistically enhances MSC cardiogenesis. Although TSA by itself had no effect on cardiac gene expression, coaddition of TSA to MSC cultures enhanced BIX01294-induced levels of Mesp1 and brachyury expression 5.6- and 7.2-fold. Moreover, MSCs exposed to the cardiogenic stimulus Wnt11 generated 2.6- to 5.6-fold higher levels of the cardiomyocyte markers GATA4, Nkx2.5, and myocardin when pretreated with TSA in addition to BIX01294. MSC cultures also showed a corresponding increase in the prevalence of sarcomeric protein-positive cells when treated with these small molecule inhibitors. These results correlated with data showing synergism between (1) TSA and BIX01294 in promoting acetylation of lysine 27 on histone H3 and (2) BIX01294 and Wnt11 in decreasing β-catenin accumulation in MSCs. The implications of these findings are discussed in light of observations in the early embryo on the importance of β-catenin signaling and histone modifications for cardiomyocyte differentiation and heart development. |
| format | Article |
| id | doaj-art-80fa8886eb334e36b84c4af0fd27443e |
| institution | Kabale University |
| issn | 1687-966X 1687-9678 |
| language | English |
| publishDate | 2017-01-01 |
| publisher | Wiley |
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| series | Stem Cells International |
| spelling | doaj-art-80fa8886eb334e36b84c4af0fd27443e2025-02-03T06:00:50ZengWileyStem Cells International1687-966X1687-96782017-01-01201710.1155/2017/34649533464953Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow CellsJinpu Yang0Keerat Kaur1John G. Edwards2Carol A. Eisenberg3Leonard M. Eisenberg4New York Medical College/Westchester Medical Center Stem Cell Laboratory, Departments of Physiology and Medicine, New York Medical College, Valhalla, NY 10595, USANew York Medical College/Westchester Medical Center Stem Cell Laboratory, Departments of Physiology and Medicine, New York Medical College, Valhalla, NY 10595, USADepartment of Physiology, New York Medical College, Valhalla, NY 10595, USANew York Medical College/Westchester Medical Center Stem Cell Laboratory, Departments of Physiology and Medicine, New York Medical College, Valhalla, NY 10595, USANew York Medical College/Westchester Medical Center Stem Cell Laboratory, Departments of Physiology and Medicine, New York Medical College, Valhalla, NY 10595, USAPreviously, we reported that treatment with the G9a histone methyltransferase inhibitor BIX01294 causes bone marrow mesenchymal stem cells (MSCs) to exhibit a cardiocompetent phenotype, as indicated by the induction of the precardiac markers Mesp1 and brachyury. Here, we report that combining the histone deacetylase inhibitor trichostatin A (TSA) with BIX01294 synergistically enhances MSC cardiogenesis. Although TSA by itself had no effect on cardiac gene expression, coaddition of TSA to MSC cultures enhanced BIX01294-induced levels of Mesp1 and brachyury expression 5.6- and 7.2-fold. Moreover, MSCs exposed to the cardiogenic stimulus Wnt11 generated 2.6- to 5.6-fold higher levels of the cardiomyocyte markers GATA4, Nkx2.5, and myocardin when pretreated with TSA in addition to BIX01294. MSC cultures also showed a corresponding increase in the prevalence of sarcomeric protein-positive cells when treated with these small molecule inhibitors. These results correlated with data showing synergism between (1) TSA and BIX01294 in promoting acetylation of lysine 27 on histone H3 and (2) BIX01294 and Wnt11 in decreasing β-catenin accumulation in MSCs. The implications of these findings are discussed in light of observations in the early embryo on the importance of β-catenin signaling and histone modifications for cardiomyocyte differentiation and heart development.http://dx.doi.org/10.1155/2017/3464953 |
| spellingShingle | Jinpu Yang Keerat Kaur John G. Edwards Carol A. Eisenberg Leonard M. Eisenberg Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells Stem Cells International |
| title | Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells |
| title_full | Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells |
| title_fullStr | Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells |
| title_full_unstemmed | Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells |
| title_short | Inhibition of Histone Methyltransferase, Histone Deacetylase, and β-Catenin Synergistically Enhance the Cardiac Potential of Bone Marrow Cells |
| title_sort | inhibition of histone methyltransferase histone deacetylase and β catenin synergistically enhance the cardiac potential of bone marrow cells |
| url | http://dx.doi.org/10.1155/2017/3464953 |
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