The regulation of telomere length (TL) is a complex process, requiring the telomerase enzyme complex and numerous regulatory proteins. Epigenetic regulation may also be important in telomere maintenance. Specifically, methylation at subtelomeres is associated with changes in TL in vitro and in mouse models. Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome characterized by exceedingly short telomeres and mutations in telomere biology genes. To understand the interaction between methylation and TL in humans, we measured LINE‐1, pericentromeric (NBL2), and subtelomeric (D4Z4) methylation in peripheral blood DNA derived from 40 patients with DC and 51 mutation‐negative relatives. Pearson’s correlation coefficient and linear regression models were used to evaluate the relationship between age‐standardized lymphocyte TL measured by flow FISH and % DNA methylation. No differences in % subtelomeric, LINE‐1, or pericentromeric methylation between patients with DC and relatives were noted except for an increase in % subtelomeric methylation in DC patients with a telomerase‐complex mutation (TERC, TERT, DKC1, or TCAB1) (63.0% in DC vs. 61.8% in relatives, P = 0.03). Positive correlations between TL and DNA methylation at LINE‐1 (r = 0.39, P = 0.01) and subtelomeric (r = 0.32, P = 0.05) sites were present in patients with DC. The positive correlation between TL and % LINE‐1 methylation was restricted to TINF2 mutations. In contrast, statistically nonsignificant inverse correlations between TL and % LINE‐1 (r = −0.17), subtelomeric (r = −0.20) were present in unaffected relatives. This study suggests an interaction between TL and both subtelomeric and LINE‐1 methylation, which may be altered based on mutation status of telomere biology genes.

中文翻译：

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先天性角化不良DNA甲基化与端粒长度的关系。

端粒长度 (TL) 的调节是一个复杂的过程，需要端粒酶复合物和众多调节蛋白。表观遗传调控在端粒维持中也可能很重要。具体而言，亚端粒的甲基化与体外TL 的变化有关并在小鼠模型中。先天性角化不良 (DC) 是一种遗传性骨髓衰竭综合征，其特征是端粒极短和端粒生物学基因突变。为了了解人类甲基化和 TL 之间的相互作用，我们测量了来自 40 名 DC 患者和 51 名突变阴性亲属的外周血 DNA 中的 LINE-1、着丝粒周围 (NBL2) 和亚端粒 (D4Z4) 甲基化。Pearson 相关系数和线性回归模型用于评估通过 FISH 测量的年龄标准化淋巴细胞 TL 与 DNA 甲基化百分比之间的关系。除了端粒酶复合物突变的 DC 患者的亚端粒甲基化百分比增加外，DC 患者和亲属之间的亚端粒、LINE-1 或着丝粒周围甲基化百分比没有差异。TERC、TERT、DKC1或TCAB1）（DC 中的 63.0% 与亲属中的 61.8%，P  = 0.03）。 DC 患者中存在LINE-1 ( r  = 0.39, P  = 0.01) 和亚端粒 ( r  = 0.32, P = 0.05) 位点的TL 和 DNA 甲基化之间的正相关。TL 和 % LINE-1 甲基化之间的正相关仅限于TINF2突变。相比之下，TL 和 % LINE-1 ( r  = -0.17)、亚端粒 ( r = -0.20) 存在于未受影响的亲属中。这项研究表明 TL 与亚端粒和 LINE-1 甲基化之间存在相互作用，这可能会根据端粒生物学基因的突变状态而改变。