Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing.
Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing.
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DOI：
10.1016/j.devcel.2014.03.004
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发表时间：
2014-04-14
影响因子：
11.8
通讯作者：
Liu L
中科院分区：
文献类型：
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作者：
Dan J;Liu Y;Liu N;Chiourea M;Okuka M;Wu T;Ye X;Mou C;Wang L;Wang L;Yin Y;Yuan J;Zuo B;Wang F;Li Z;Pan X;Yin Z;Chen L;Keefe DL;Gagos S;Xiao A;Liu L
端粒长度的稳定对于胚胎干细胞(ESCs)的基因组稳定性和无限自我更新至关重要。我们发现，端粒相关蛋白Rif1需要通过负向调节Zscan4的表达来维持端粒长度的动态平衡，Zscan4是端粒重组延长的关键因素。Rif1缺失导致末端超重组、端粒长度异质性和染色体融合。通过shRNA降低Zscan4可以显著挽救Rif1缺失的ESCs的端粒重组缺陷和相关的胚胎死亡。此外，Rif1通过维持亚端粒区域H3K9me3的水平来负向调节Zscan4的表达。从机制上讲，Rif1相互作用并稳定H3K9甲基化复合体。因此，Rif1通过介导异染色质沉默来调节ESCs的端粒长度稳态。
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.