Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
Epigenetics. 2013 May;8(5):512-21. doi: 10.4161/epi.24450. Epub 2013 Apr 17.
Subtelomeres are patchworks of evolutionary conserved sequence blocks and harbor the transcriptional start sites for telomere repeat containing RNAs (TERRA). Recent studies suggest that the interplay between telomeres and subtelomeric chromatin is required for maintaining telomere function. To further characterize chromatin remodeling of subtelomeres in relation to telomere shortening and cellular senescence, we systematically quantified histone modifications and DNA methylation at the subtelomeres of chromosomes 7q and 11q in primary human WI-38 fibroblasts. Upon senescence, both subtelomeres were characterized by a decrease in markers of constitutive heterochromatin, suggesting relative chromatin relaxation. However, we did not find increased levels of markers of euchromatin or derepression of the 7q VIPR2 gene. The repressed state of the subtelomeres was maintained upon senescence, which could be attributed to a rise in levels of facultative heterochromatin markers at both subtelomeres. While senescence-induced subtelomeric chromatin remodeling was similar for both chromosomes, chromatin remodeling at TERRA promoters displayed chromosome-specific patterns. At the 7q TERRA promoter, chromatin structure was co-regulated with the more proximal subtelomere. In contrast, the 11q TERRA promoter, which was previously shown to be bound by CCCTC-binding factor CTCF, displayed lower levels of markers of constitutive heterochromatin that did not change upon senescence, whereas levels of markers of facultative heterochromatin decreased upon senescence. In line with the chromatin state data, transcription of 11q TERRA but not 7q TERRA was detected. Our study provides a detailed description of human subtelomeric chromatin dynamics and shows distinct regulation of the TERRA promoters of 7q and 11q upon cellular senescence.
端粒是进化保守序列块的拼凑物，并且包含端粒重复序列 RNA（TERRA）的转录起始位点。最近的研究表明，端粒和端粒外染色质之间的相互作用是维持端粒功能所必需的。为了进一步描述与端粒缩短和细胞衰老有关的端粒外染色质重塑，我们系统地定量了染色体 7q 和 11q 端粒外的组蛋白修饰和 DNA 甲基化在原代人 WI-38 成纤维细胞中。在衰老过程中，两个端粒外都表现出组成性异染色质标记物减少的特征，表明相对染色质松弛。然而，我们没有发现常染色质标记物水平增加或 7q VIPR2 基因的去抑制。在衰老过程中端粒外的抑制状态得以维持，这可能归因于两个端粒外的兼性异染色质标记物水平升高。虽然两种染色体的衰老诱导的端粒外染色质重塑相似，但 TERRA 启动子处的染色质重塑表现出染色体特异性模式。在 7q TERRA 启动子处，染色质结构与更靠近端粒外的区域共同调节。相比之下，先前被证明由 CCCTC 结合因子 CTCF 结合的 11q TERRA 启动子，其组成性异染色质标记物水平较低，且在衰老过程中不会改变，而兼性异染色质标记物水平在衰老过程中下降。与染色质状态数据一致，检测到 11q TERRA 的转录，但未检测到 7q TERRA 的转录。我们的研究提供了人类端粒外染色质动力学的详细描述，并显示了细胞衰老时 7q 和 11q 的 TERRA 启动子的明显调节。
