title: Rif1 maintains telomere length homeostasis of ESCs by mediating heterochromatin silencing.
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.
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Jiameng
authors.initials: J
authors.lastname: Dan
authors.affiliation: Yale Stem Cell Center and Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Na
authors.initials: N
authors.lastname: Liu
authors.affiliation: Laboratory of Genetics, Center of Basic Research II, Biomedical Research Foundation of the Academy of Athens Greece (BRFAA), Soranou Efesiou 4, Athens 11527, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Chiourea
authors.affiliation: Department of Obstetrics and Gynecology, University of South Florida College of Medicine, Tampa, FL 33612, USA.
authors.forename: Maja
authors.initials: M
authors.lastname: Okuka
authors.affiliation: Yale Stem Cell Center and Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Chunlin
authors.initials: C
authors.lastname: Mou
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Lingling
authors.initials: L
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Jihong
authors.initials: J
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Bingfeng
authors.initials: B
authors.lastname: Zuo
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: Yale Stem Cell Center and Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, USA.
authors.forename: Xinghua
authors.initials: X
authors.lastname: Pan
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Zhinan
authors.initials: Z
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Medicinal Chemical Biology, Department of Cell Biology and Genetics, College of Life Sciences, Nankai University, Tianjin 300071, China.
authors.forename: Lingyi
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, New York University Langone Medical Center, New York, NY 10016, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Keefe
authors.affiliation: Laboratory of Genetics, Center of Basic Research II, Biomedical Research Foundation of the Academy of Athens Greece (BRFAA), Soranou Efesiou 4, Athens 11527, Greece.
authors.forename: Sarantis
authors.initials: S
authors.lastname: Gagos
authors.affiliation: Yale Stem Cell Center and Department of Genetics, Yale University School of Medicine, New Haven, CT 06519, USA. Electronic address: andrew.xiao@yale.edu.
authors.forename: Andrew
authors.initials: A
authors.lastname: Xiao
authors.affiliation: State 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
mesh_terms: D000818:Animals; D053595:Embryonic Stem Cells / Q000378:metabolism* / Q000502:physiology; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D008745:Methylation; D051379:Mice; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011995:Recombination, Genetic; D016615:Telomere / Q000235:genetics / Q000378:metabolism; D059505:Telomere Homeostasis; D034501:Telomere-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D006570:Heterochromatin; D006657:Histones; D012333:RNA, Messenger; C492748:Rif1 protein, mouse; D034501:Telomere-Binding Proteins; D014157:Transcription Factors; C000588925:Zscan4c protein, mouse
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