Dan Jiameng, Yang Jiao, Liu Yifei, Xiao Andrew, Liu Lin
State Key Laboratory of Medicinal Chemical Biology, Collaborative Innovation Center for Biotherapy, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin, China.
Yale Stem Cell Center and Department of Genetics, Yale University School of Medicine, New Haven, Connecticut.
J Cell Physiol. 2015 Oct;230(10):2337-44. doi: 10.1002/jcp.24980.
Mammalian telomeres and subtelomeres are marked by heterochromatic epigenetic modifications, including repressive DNA methylation and histone methylation (e.g., H3K9me3 and H4K20me3). Loss of these epigenetic marks results in increased rates of telomere recombination and elongation. Other than these repressive epigenetic marks, telomeric and subtelomeric H3 and H4 are underacetylated. Yet, whether histone acetylation also regulates telomere length has not been directly addressed. We thought to test the effects of histone acetylation levels on telomere length using histone deacetylase (HDAC) inhibitor (sodium butyrate, NaB) that mediates histone hyperacetylation and histone acetyltransferase (HAT) inhibitor (C646) that mediates histone hypoacetylation. We show that histone hyperacetylation dramatically elongates telomeres in wild-type ES cells, and only slightly elongates telomeres in Terc(-/-) ES cells, suggesting that Terc is involved in histone acetylation-induced telomere elongation. In contrast, histone hypoacetylation shortens telomeres in both wild-type and Terc(-/-) ES cells. Additionally, histone hyperacetylation activates 2-cell (2C) specific genes including Zscan4, which is involved in telomere recombination and elongation, whereas histone hypoacetylation represses Zscan4 and 2C genes. These data suggest that histone acetylation levels affect the heterochromatic state at telomeres and subtelomeres, and regulate gene expression at subtelomeres, linking histone acetylation to telomere length maintenance.
哺乳动物的端粒和亚端粒具有异染色质表观遗传修饰特征，包括抑制性DNA甲基化和组蛋白甲基化（如H3K9me3和H4K20me3）。这些表观遗传标记的缺失会导致端粒重组和延长速率增加。除了这些抑制性表观遗传标记外，端粒和亚端粒的H3和H4处于低乙酰化状态。然而，组蛋白乙酰化是否也调节端粒长度尚未得到直接验证。我们想用介导组蛋白高乙酰化的组蛋白去乙酰化酶（HDAC）抑制剂（丁酸钠，NaB）和介导组蛋白低乙酰化的组蛋白乙酰转移酶（HAT）抑制剂（C646）来测试组蛋白乙酰化水平对端粒长度的影响。我们发现，组蛋白高乙酰化在野生型胚胎干细胞中显著延长端粒，而在Terc（-/-）胚胎干细胞中仅轻微延长端粒，这表明Terc参与了组蛋白乙酰化诱导的端粒延长。相反，组蛋白低乙酰化在野生型和Terc（-/-）胚胎干细胞中均缩短端粒。此外，组蛋白高乙酰化激活包括Zscan4在内的2细胞（2C）特异性基因，Zscan4参与端粒重组和延长，而组蛋白低乙酰化则抑制Zscan4和2C基因。这些数据表明，组蛋白乙酰化水平影响端粒和亚端粒的异染色质状态，并调节亚端粒处的基因表达，将组蛋白乙酰化与端粒长度维持联系起来。
