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

2017 ◽  
Vol 2017 ◽  
pp. 1-15
Author(s):  
Jinpu Yang ◽  
Keerat Kaur ◽  
John G. Edwards ◽  
Carol A. Eisenberg ◽  
Leonard M. Eisenberg
Keyword(s):  
Bone Marrow ◽  
Histone Deacetylase ◽  
Heart Development ◽  
Bone Marrow Cells ◽  
Trichostatin A ◽  
Histone Methyltransferase ◽  
Early Embryo ◽  
Sarcomeric Protein ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Cardiac Gene

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.

scholarly journals Inhibition of G9a Histone Methyltransferase Converts Bone Marrow Mesenchymal Stem Cells to Cardiac Competent Progenitors

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Jinpu Yang ◽  
Keerat Kaur ◽  
Li Lin Ong ◽  
Carol A. Eisenberg ◽  
Leonard M. Eisenberg
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Bone Marrow Cells ◽  
Histone Methyltransferase ◽  
Stem Cell Population ◽  
Molecular Profile ◽  
Sarcomeric Protein ◽  
Marrow Mesenchymal Stem Cells ◽  
Marrow Cells

The G9a histone methyltransferase inhibitor BIX01294 was examined for its ability to expand the cardiac capacity of bone marrow cells. Inhibition of G9a histone methyltransferase by gene specific knockdown or BIX01294 treatment was sufficient to induce expression of precardiac markersMesp1andbrachyuryin bone marrow cells. BIX01294 treatment also allowed bone marrow mesenchymal stem cells (MSCs) to express the cardiac transcription factorsNkx2.5,GATA4, andmyocardinwhen subsequently exposed to the cardiogenic stimulating factor Wnt11. Incubation of BIX01294-treated MSCs with cardiac conditioned media provoked formation of phase bright cells that exhibited a morphology and molecular profile resembling similar cells that normally form from cultured atrial tissue. Subsequent aggregation and differentiation of BIX01294-induced, MSC-derived phase bright cells provoked their cardiomyogenesis. This latter outcome was indicated by their widespread expression of the primary sarcomeric proteins muscleα-actinin and titin. MSC-derived cultures that were not initially treated with BIX01294 exhibited neither a commensurate burst of phase bright cells nor stimulation of sarcomeric protein expression. Collectively, these data indicate that BIX01294 has utility as a pharmacological agent that could enhance the ability of an abundant and accessible stem cell population to regenerate new myocytes for cardiac repair.

Coinduction of Embryonic and Adult-Type Globin mRNAs by Sodium Butyrate and Trichostatin A in Two Murine Interleukin-3–Dependent Bone Marrow–Derived Cell Lines

Blood ◽  
1998 ◽  
Vol 92 (11) ◽  
pp. 4383-4393 ◽  
Author(s):  
Kimiko Ishiguro ◽  
Alan C. Sartorelli
Keyword(s):  
Bone Marrow ◽  
Histone Deacetylase ◽  
Cell Lines ◽  
Sodium Butyrate ◽  
Trichostatin A ◽  
Globin Genes ◽  
Globin Mrna ◽  
Interleukin 3 ◽  
Mrna Species ◽  
Major Species

Abstract Using an RNase protection assay, globin mRNA species expressed in clones derived from Ba/F3 and B6SUtA cells transfected with the erythropoietin receptor (EpoR) and selected with erythropoietin (Epo) were compared with globin mRNA species induced in corresponding parental cells by sodium butyrate (SB) and trichostatin A (TSA). βMajor/βminor- and -1/-2–globin mRNAs were the major species, with trace amounts of ɛ-globin mRNA, formed in Epo-stimulated EpoR+ Ba/F3 clones, whereas SB and TSA allowed expression of all species of globin mRNAs, ie, ɛ, βh1, βmajor/βminor, ζ, and -1/-2, in parental Ba/F3 cells. In contrast, ɛ- and -1/-2–globin mRNAs were the major species present in Epo-stimulated EpoR+ B6SUtA clones, whereas SB and TSA activated ɛ-, βh1-, βS/βT-, and -1/-2–globin genes in parental B6SUtA cells; ζ-globin mRNA was not detected in SB- and TSA-treated B6SUtA cells. Because TSA is a specific inhibitor of histone deacetylase, the mimicry of action exhibited by SB and TSA suggests that the effects of SB are mediated through its ability to inhibit histone deacetylase and that histone deacetylase is an integral part of the repression of globin genes in these interleukin-3–dependent cells. Efficient coinduction of embryonic and adult types of globin mRNA in bone marrow cell lines derived from adult mice indicates that adult hematopoietic precursors possess an embryonic nature. These cell lines are useful models to study the mechanism(s) of developmental globin gene switching.

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