Rif1 通过介导异染色质沉默来维持 ESC 的端粒长度稳态。
Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing.
机构信息
State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
Yale Stem Cell Center and Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, USA.
出版信息
Dev Cell. 2014 Apr 14;29(1):7-19. doi: 10.1016/j.devcel.2014.03.004.
Abstract
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.
摘要
端粒长度的稳定对于基因组的稳定性和胚胎干细胞（ESCs）的无限自我更新至关重要。我们发现，端粒相关蛋白 Rif1 通过负调控端粒伸长的关键因素——重组因子 Zscan4 的表达，来维持端粒长度的稳定。 Rif1 的缺失会导致末端超重组、端粒长度异质性和染色体融合。通过 shRNA 减少 Zscan4 的表达，可显著挽救 Rif1 缺失的 ESCs 的端粒重组缺陷，并挽救相关的胚胎致死性。此外，Rif1 通过维持着丝粒区域的 H3K9me3 水平来负调控 Zscan4 的表达。从机制上讲， Rif1 与 H3K9 甲基化复合物相互作用并稳定其活性。因此，Rif1 通过介导异染色质沉默来调节 ESCs 的端粒长度稳定。
相似文献
1
Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing.Rif1 通过介导异染色质沉默来维持 ESC 的端粒长度稳态。
Dev Cell. 2014 Apr 14;29(1):7-19. doi: 10.1016/j.devcel.2014.03.004.
2
A tight control of Rif1 by Oct4 and Smad3 is critical for mouse embryonic stem cell stability.Oct4和Smad3对Rif1的严格调控对小鼠胚胎干细胞的稳定性至关重要。
Cell Death Dis. 2015 Jan 8;6(1):e1588. doi: 10.1038/cddis.2014.551.
3
Depleting components of the THO complex causes increased telomere length by reducing the expression of the telomere-associated protein Rif1p.耗尽 THO 复合物的成分会通过降低端粒相关蛋白 Rif1p 的表达来增加端粒长度。
PLoS One. 2012;7(3):e33498. doi: 10.1371/journal.pone.0033498. Epub 2012 Mar 20.
4
Zscan4 Contributes to Telomere Maintenance in Telomerase-Deficient Late Generation Mouse ESCs and Human ALT Cancer Cells.Zscan4 有助于端粒酶缺陷的晚期世代小鼠胚胎干细胞和人类 ALT 癌细胞中端粒的维持。
Cells. 2022 Jan 28;11(3):456. doi: 10.3390/cells11030456.
5
Rif1 promotes a repressive chromatin state to safeguard against endogenous retrovirus activation.Rif1促进一种抑制性染色质状态，以防止内源性逆转录病毒激活。
Nucleic Acids Res. 2017 Dec 15;45(22):12723-12738. doi: 10.1093/nar/gkx884.
6
Zscan4 Inhibits Maintenance DNA Methylation to Facilitate Telomere Elongation in Mouse Embryonic Stem Cells.Zscan4 通过抑制维持性 DNA 甲基化促进小鼠胚胎干细胞端粒延长。
Cell Rep. 2017 Aug 22;20(8):1936-1949. doi: 10.1016/j.celrep.2017.07.070.
7
Deletion of the major peroxiredoxin Tsa1 alters telomere length homeostasis.主要过氧化物酶 Tsa1 的缺失改变端粒长度的动态平衡。
Aging Cell. 2013 Aug;12(4):635-44. doi: 10.1111/acel.12085. Epub 2013 May 15.
8
Taz1, Rap1 and Rif1 act both interdependently and independently to maintain telomeres.端粒蛋白Taz1、Rap1和Rif1相互依赖且独立地发挥作用以维持端粒。
EMBO J. 2005 Sep 7;24(17):3128-35. doi: 10.1038/sj.emboj.7600779. Epub 2005 Aug 11.
9
Pold3 is required for genomic stability and telomere integrity in embryonic stem cells and meiosis.Pold3 对于胚胎干细胞的基因组稳定性和端粒完整性以及减数分裂是必需的。
Nucleic Acids Res. 2018 Apr 20;46(7):3468-3486. doi: 10.1093/nar/gky098.
10
Functional diversification of yeast telomere associated protein, Rif1, in higher eukaryotes.酵母端粒相关蛋白 Rif1 在高等真核生物中的功能多样化。
BMC Genomics. 2012 Jun 19;13:255. doi: 10.1186/1471-2164-13-255.
引用本文的文献
1
BMAL1-TRIM28 represses transposable elements independently of CLOCK in pluripotent cells.在多能细胞中，BMAL1-TRIM28独立于CLOCK抑制转座元件。
Nat Commun. 2025 Sep 10;16(1):8250. doi: 10.1038/s41467-025-63778-4.
2
Nat10 maintains the homeostasis of pluripotent and 2-cell-like states in mouse embryonic stem cells through mRNA cytidine acetylation.Nat10通过mRNA胞嘧啶乙酰化维持小鼠胚胎干细胞中多能性和2细胞样状态的稳态。
Nucleic Acids Res. 2025 Jun 6;53(11). doi: 10.1093/nar/gkaf504.
3
RIF1 controls replication timing in early mouse embryos independently of lamina-associated nuclear organization.RIF1独立于与核纤层相关的核组织调控小鼠早期胚胎中的复制时间。
Dev Cell. 2025 Apr 16. doi: 10.1016/j.devcel.2025.03.016.
4
The ZBTB24-CDCA7-HELLS axis suppresses the totipotent 2C-like reprogramming by maintaining Dux methylation and repression.ZBTB24-CDCA7-HELLS轴通过维持Dux甲基化和抑制来抑制全能性2C样重编程。
Nucleic Acids Res. 2025 Apr 10;53(7). doi: 10.1093/nar/gkaf302.
5
RIF1 integrates DNA repair and transcriptional requirements during the establishment of humoral immune responses.在体液免疫反应建立过程中，RIF1整合DNA修复和转录需求。
Nat Commun. 2025 Jan 17;16(1):777. doi: 10.1038/s41467-025-56166-5.
6
Repetitive Sequence Stability in Embryonic Stem Cells.胚胎干细胞中的重复序列稳定性。
Int J Mol Sci. 2024 Aug 13;25(16):8819. doi: 10.3390/ijms25168819.
7
Novel role for Ddx39 in differentiation and telomere length regulation of embryonic stem cells.Ddx39 在胚胎干细胞分化和端粒长度调控中的新作用。
Cell Death Differ. 2024 Nov;31(11):1534-1544. doi: 10.1038/s41418-024-01354-x. Epub 2024 Aug 6.
8
UBQLN1 links proteostasis and mitochondria function to telomere maintenance in human embryonic stem cells.UBQLN1 将蛋白稳态和线粒体功能与人类胚胎干细胞中的端粒维持联系起来。
Stem Cell Res Ther. 2024 Jun 21;15(1):180. doi: 10.1186/s13287-024-03789-y.
9
A comprehensive review: synergizing stem cell and embryonic development knowledge in mouse and human integrated stem cell-based embryo models.全面综述：在基于小鼠和人类整合干细胞的胚胎模型中融合干细胞与胚胎发育知识
Front Cell Dev Biol. 2024 Apr 22;12:1386739. doi: 10.3389/fcell.2024.1386739. eCollection 2024.
10
TNRC18 engages H3K9me3 to mediate silencing of endogenous retrotransposons.TNRC18 通过与 H3K9me3 结合来介导内源性反转录转座子的沉默。
Nature. 2023 Nov;623(7987):633-642. doi: 10.1038/s41586-023-06688-z. Epub 2023 Nov 8.
本文引用的文献
1
An ENU mutagenesis screen identifies novel and known genes involved in epigenetic processes in the mouse.一项ENU诱变筛选鉴定出了参与小鼠表观遗传过程的新基因和已知基因。
Genome Biol. 2013;14(9):R96. doi: 10.1186/gb-2013-14-9-r96.
2
Rif1 and Rif2 shape telomere function and architecture through multivalent Rap1 interactions. Rif1 和 Rif2 通过多价 Rap1 相互作用塑造端粒功能和结构。
Cell. 2013 Jun 6;153(6):1340-53. doi: 10.1016/j.cell.2013.05.007.
3
53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions.53BP1 通过不同的磷酸化蛋白相互作用介导有性和诱变 DNA 修复。
Cell. 2013 Jun 6;153(6):1266-80. doi: 10.1016/j.cell.2013.05.023. Epub 2013 May 30.
4
A cell cycle-dependent regulatory circuit composed of 53BP1-RIF1 and BRCA1-CtIP controls DNA repair pathway choice.一个由 53BP1-RIF1 和 BRCA1-CtIP 组成的细胞周期依赖性调控回路控制 DNA 修复途径的选择。
Mol Cell. 2013 Mar 7;49(5):872-83. doi: 10.1016/j.molcel.2013.01.001. Epub 2013 Jan 17.
5
RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection.RIF1 对于 53BP1 依赖性非同源末端连接和抑制 DNA 双链断裂切除是必需的。
Mol Cell. 2013 Mar 7;49(5):858-71. doi: 10.1016/j.molcel.2013.01.002. Epub 2013 Jan 17.
6
Rif1 prevents resection of DNA breaks and promotes immunoglobulin class switching. Rif1 防止 DNA 断裂的切除，并促进免疫球蛋白类别转换。
Science. 2013 Feb 8;339(6120):711-5. doi: 10.1126/science.1230624. Epub 2013 Jan 10.
7
53BP1 regulates DSB repair using Rif1 to control 5' end resection.53BP1 通过 Rif1 控制 5' 端切除来调节 DSB 修复。
Science. 2013 Feb 8;339(6120):700-4. doi: 10.1126/science.1231573. Epub 2013 Jan 10.
8
Acute stress and hippocampal histone H3 lysine 9 trimethylation, a retrotransposon silencing response.急性应激和海马体组蛋白 H3 赖氨酸 9 三甲基化，一种逆转录转座子沉默反应。
Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17657-62. doi: 10.1073/pnas.1215810109. Epub 2012 Oct 4.
9
Rif1 regulates the replication timing domains on the human genome. Rif1 调节人类基因组上的复制时间域。
EMBO J. 2012 Sep 12;31(18):3667-77. doi: 10.1038/emboj.2012.180. Epub 2012 Jul 31.
10
Mouse Rif1 is a key regulator of the replication-timing programme in mammalian cells.鼠 Rif1 是哺乳动物细胞复制定时程序的关键调节因子。
EMBO J. 2012 Sep 12;31(18):3678-90. doi: 10.1038/emboj.2012.214. Epub 2012 Jul 31.
Zotero 插件