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Dev Cell. 2014 Apr 14;29(1):7-19. doi: 10.1016/j.devcel.2014.03.004.

Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing.

Author information

  • 1State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
  • 2Yale Stem Cell Center and Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, USA.
  • 3Laboratory of Genetics, Center of Basic Research II, Biomedical Research Foundation of the Academy of Athens Greece (BRFAA), SoranouĀ Efesiou 4, Athens 11527, Greece.
  • 4Department of Obstetrics and Gynecology, University of South Florida College of Medicine, Tampa, FL 33612, USA.
  • 5Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY 10016, USA.
  • 6Yale Stem Cell Center and Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, USA. Electronic address: andrew.xiao@yale.edu.
  • 7State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China. Electronic address: liulin@nankai.edu.cn.

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.

Copyright Ā© 2014 Elsevier Inc. All rights reserved.

PMID:
24735877
[PubMed - indexed for MEDLINE]
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