Distinct patterns of histone modifications at cardiac-specific gene promoters between cardiac stem cells and mesenchymal stem cells.
Distinct patterns of histone modifications at cardiac-specific gene promoters between cardiac stem cells and mesenchymal stem cells.
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DOI：
10.1152/ajpcell.00359.2012
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发表时间：
2013-06
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影响因子：
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通讯作者：
Meijing Wang;Qing Yu;Lina Wang;Hongmei Gu
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作者：
Meijing Wang;Qing Yu;Lina Wang;Hongmei Gu
间充质干细胞（MSC）和心脏干细胞（CSC）具有不同的发育成心肌细胞的潜力。间充质干细胞和癌症干细胞的心肌生成能力的机制仍然难以捉摸。众所周知，组蛋白修饰与基因表达相关并有助于细胞命运的决定。在这里，我们假设特定的组蛋白修饰伴随心脏特异性基因表达，从而决定 MSC 和 CSC 向心脏细胞的分化能力。我们的结果表明，在心脏特异性基因（Myh6、Myl2、Actc1、Tnni3和Tnnt2）的启动子区域，作为基因激活标志的H3（acH3）和H4（acH4）组蛋白乙酰化水平在CSC（Sca-1（+）CD29（+））中高于MSC。此外，与 MSC 相比，CSC 中心脏特异性基因启动子区域的组蛋白脱乙酰酶 (HDAC) 1 和 HDAC2 结合水平较低。使用曲古抑菌素 A（一种 HDAC 抑制剂）治疗可上调 MSC 中心脏特异性基因的表达。小干扰RNA抑制HDAC1或HDAC2表达导致心脏基因表达增加，并伴随着基因位点acH3和acH4水平的增强。我们得出的结论是，CSC 中心脏特异性基因位点的组蛋白乙酰化水平高于 MSC，这反映出 CSC 发育成心肌细胞的潜力更强。这些谱系差异组蛋白修饰可能是由于 CSC 中心脏特异性基因启动子处的 HDAC 招募少于 MSC。
Mesenchymal stem cells (MSCs) and cardiac stem cells (CSCs) possess different potential to develop into cardiomyocytes. The mechanism underlying cardiomyogenic capacity of MSCs and CSCs remains elusive. It is well established that histone modifications correlate with gene expression and contribute to cell fate commitment. Here we hypothesize that specific histone modifications accompany cardiac-specific gene expression, thus determining the differentiation capacity of MSCs and CSCs toward heart cells. Our results indicate that, at the promoter regions of cardiac-specific genes (Myh6, Myl2, Actc1, Tnni3, and Tnnt2), the levels of histone acetylation of H3 (acH3) and H4 (acH4), as a mark indicative of gene activation, were higher in CSCs (Sca-1(+)CD29(+)) than MSCs. Additionally, lower binding levels of histone deacetylase (HDAC) 1 and HDAC2 at promoter regions of cardiac-specific genes were noticed in CSCs than MSCs. Treatment with trichostatin A, an HDAC inhibitor, upregulated cardiac-specific gene expression in MSCs. Suppression of HDAC1 or HDAC2 expression by small interfering RNAs led to increased cardiac gene expression and was accompanied by enhanced acH3 and acH4 levels at gene loci. We conclude that greater levels of histone acetylation at cardiac-specific gene loci in CSCs than MSCs reflect a stronger potential for CSCs to develop into cardiomyocytes. These lineage-differential histone modifications are likely due to less HDAC recruitment at cardiac-specific gene promoters in CSCs than MSCs.