Rif1 Maintains Telomere Length Homeostasis of ESCs by Mediating Heterochromatin Silencing

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• 作者：Jiameng Dan¹ ; ⁶ ; Yifei Liu² ; ⁶ ; Na Liu¹ ; ⁶ ; Maria Chiourea³ ; Maja Okuka⁴ ; Tao Wu² ; Xiaoying Ye¹ ; Chunlin Mou¹ ; Lei Wang¹ ; Lingling Wang¹ ; Yu Yin¹ ; Jihong Yuan¹ ; Bingfeng Zuo¹ ; Fang Wang¹ ; Zhiguo Li¹ ; Xinghua Pan² ; Zhinan Yin¹ ; Lingyi Chen¹ ; David L. Keefe⁵ ; Sarantis Gagos³ ; Andrew Xiao² ; ^{andrew.xiao@yale.edu" class="auth_mail} ; Lin Liu¹ ; ^{liulin@nankai.edu.cn" class="auth_mail}
• 刊名：Developmental Cell
• 出版年：14 April, 2014
• 年：2014
• 卷：29
• 期：1
• 页码：7-19
• 全文大小：3669 K

文摘

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Summary

Telomere length homeostasis is essential for genomic stability and unlimited self-renewal of embryonic stem cells (ESCs). We show that telomere-associated protein Rif1 is required to maintain telomere length homeostasis by negatively regulating Zscan4 expression, a critical factor for telomere elongation by recombination. Depletion of Rif1 results in terminal hyperrecombination, telomere length heterogeneity, and chromosomal fusions. Reduction of Zscan4 by shRNA significantly rescues telomere recombination defects of Rif1-depleted ESCs and associated embryonic lethality. Further, Rif1 negatively modulates Zscan4 expression by maintaining H3K9me3 levels at subtelomeric regions. Mechanistically, Rif1 interacts and stabilizes H3K9 methylation complex. Thus, Rif1 regulates telomere length homeostasis of ESCs by mediating heterochromatic silencing.