HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage
HDAC activity regulates entry of mesoderm cells into the cardiac muscle lineage
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DOI：
10.1242/jcs.03185
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发表时间：
2006-10-15
影响因子：
4
通讯作者：
Skerjanc, Ilona S.
中科院分区：
文献类型：
--
作者：
Karamboulas, Christina;Swedani, Albert;Skerjanc, Ilona S.
II类组蛋白去乙酰化酶（HDAC4、HDAC5、HDAC7和HDAC9）已被证明与肌细胞增强因子2（MEF2s）相互作用，并在心肌肥大的抑制中起重要作用。我们研究了HDACs在P19胚胎癌干细胞分化为心肌细胞过程中的作用。用HDAC抑制剂曲古抑菌素A处理聚集的P19细胞，诱导中胚层细胞进入心肌谱系，这通过转录本Nkx2 - 5、MEF2C、GATA4和心肌α - 肌动蛋白的上调得以证明。此外，HDAC4的过表达抑制心肌发生，这通过心肌基因表达的下调得以体现。II类HDAC活性通过Ca²⁺/钙调蛋白依赖性激酶（CaMK）磷酸化而被抑制。在P19细胞中表达活化的CaMKIV会上调Nkx2 - 5、GATA4和MEF2C的表达，增强心肌发育，并激活一个MEF2反应性启动子。此外，抑制CaMK信号传导会下调GATA4的表达。最后，持续表达一种显性负性形式的MEF2C（能够结合II类HDACs）的P19细胞比对照细胞更有效地进行心肌发生，这意味着一种抑制剂的解除。我们的结果表明，在一个干细胞模型系统中，HDAC活性通过抑制GATA4和Nkx2 - 5的表达来调节中胚层细胞向心肌祖细胞的分化。
Class II histone deacetylases (HDAC4, HDAC5, HDAC7 and HDAC9) have been shown to interact with myocyte enhancer factors 2 (MEF2s) and play an important role in the repression of cardiac hypertrophy. We examined the role of HDACs during the differentiation of P19 embryonic carcinoma stem cells into cardiomyoctyes. Treatment of aggregated P19 cells with the HDAC inhibitor trichostatin A induced the entry of mesodermal cells into the cardiac muscle lineage, shown by the upregulation of transcripts Nkx2-5, MEF2C, GATA4 and cardiac alpha-actin. Furthermore, the overexpression of HDAC4 inhibited cardiomyogenesis, shown by the downregulation of cardiac muscle gene expression. Class II HDAC activity is inhibited through phosphorylation by Ca2+/calmodulin-dependent kinase (CaMK). Expression of an activated CaMKIV in P19 cells upregulated the expression of Nkx2-5, GATA4 and MEF2C, enhanced cardiac muscle development, and activated a MEF2-responsive promoter. Moreover, inhibition of CaMK signaling downregulated GATA4 expression. Finally, P19 cells constitutively expressing a dominant-negative form of MEF2C, capable of binding class II HDACs, underwent cardiomyogenesis more efficiently than control cells, implying the relief of an inhibitor. Our results suggest that HDAC activity regulates the specification of mesoderm cells into cardiomyoblasts by inhibiting the expression of GATA4 and Nkx2-5 in a stem cell model system.