The most distal 2 kb region in the majority of human subtelomeres contains CpG-rich promoters for TERRA, a long non-coding RNA. When the function of the de novo DNA methyltransferase DNMT3B is disrupted, as in ICF1 syndrome, subtelomeres are abnormally hypomethylated, subtelomeric heterochromatin acquires open chromatin characteristics, TERRA is highly expressed, and telomeres shorten rapidly. In this study, we explored whether the regulation of subtelomeric epigenetic characteristics by DNMT3B is conserved between humans and mice. Studying the DNA sequence of the distal 30 kb of the majority of murine q-arm subtelomeres indicated that these regions are relatively CpG-poor and do not contain TERRA promoters similar to those present in humans. Despite the lack of human-like TERRA promoters, we clearly detected TERRA expression originating from at least seven q-arm subtelomeres, and at higher levels in mouse pluripotent stem cells in comparison to mouse embryonic fibroblasts (MEFs). However, these differences in TERRA expression could not be explained by differential methylation of CpG islands present in the TERRA-expressing murine subtelomeres. To determine whether Dnmt3b regulates the expression of TERRA in mice, we characterized subtelomeric methylation and associated telomeric functions in cells derived from ICF1 model mice. Littermate-derived WT and ICF1 MEFs demonstrated no significant differences in subtelomeric DNA methylation, chromatin modifications, TERRA expression levels, telomere sister chromatid exchange or telomere length. We conclude that the epigenetic characteristics of murine subtelomeres differ substantially from their human counterparts and that TERRA transcription in mice is regulated by factors others than Dnmt3b.

中文翻译：

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DNA甲基化对端粒功能的调节在人类和小鼠之间有所不同。

大多数人类亚端粒中最远端的 2 kb 区域包含富含 CpG 的 TERRA 启动子，TERRA 是一种长链非编码 RNA。当de novo的功能DNA 甲基转移酶 DNMT3B 被破坏，如在 ICF1 综合征中，亚端粒异常低甲基化，亚端粒异染色质获得开放染色质特征，TERRA 高度表达，端粒迅速缩短。在这项研究中，我们探讨了 DNMT3B 对亚端粒表观遗传特征的调节在人和小鼠之间是否保守。研究大多数鼠科动物 q 臂亚端粒远端 30 kb 的 DNA 序列表明，这些区域相对缺乏 CpG，并且不包含类似于人类存在的 TERRA 启动子。尽管缺乏类似人类的 TERRA 启动子，但我们清楚地检测到 TERRA 表达源自至少七个 q 臂亚端粒，并且与小鼠胚胎成纤维细胞 (MEF) 相比，在小鼠多能干细胞中的表达水平更高。然而，TERRA 表达的这些差异不能用表达 TERRA 的小鼠亚端粒中存在的 CpG 岛的差异甲基化来解释。为了确定 Dnmt3b 是否调节小鼠中 TERRA 的表达，我们表征了源自 ICF1 模型小鼠的细胞中的亚端粒甲基化和相关的端粒功能。Littermate 衍生的 WT 和 ICF1 MEF 在亚端粒 DNA 甲基化、染色质修饰、TERRA 表达水平、端粒姐妹染色单体交换或端粒长度方面没有显着差异。我们得出结论，鼠类亚端粒的表观遗传特征与其人类对应物有很大不同，并且小鼠中的 TERRA 转录受 Dnmt3b 以外的因素调节。