Division of Cardiovascular and Thoracic Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
Am J Physiol Cell Physiol. 2013 Jun 1;304(11):C1080-90. doi: 10.1152/ajpcell.00359.2012. Epub 2013 Apr 3.
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.
间充质干细胞（MSCs）和心脏干细胞（CSCs）在向心肌细胞分化的潜能上存在差异。MSCs 和 CSCs 的成心肌能力的机制仍不清楚。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着心脏特异性基因的表达，从而决定了 MSCs 和 CSCs 向心脏细胞分化的能力。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，H3（acH3）和 H4（acH4）的组蛋白乙酰化水平，作为基因激活的标志，在 CSCs（Sca-1(+)CD29(+)）中高于 MSCs。此外，在心脏特异性基因的启动子区域，HDAC1 和 HDAC2 的结合水平在 CSCs 中低于 MSCs。用组蛋白去乙酰化酶（HDAC）抑制剂 Trichostatin A 处理可上调 MSCs 中的心脏特异性基因表达。用小干扰 RNA 抑制 HDAC1 或 HDAC2 的表达可导致心脏基因表达增加，并伴随着基因座处 acH3 和 acH4 水平的增强。我们得出结论，在 CSCs 中，心脏特异性基因座上的组蛋白乙酰化水平高于 MSCs，反映了 CSCs 向心肌细胞分化的潜力更强。这些谱系差异的组蛋白修饰可能是由于在 CSCs 中，心脏特异性基因启动子上的 HDAC 募集水平低于 MSCs。
