title: Comprehensive Identification of Krüppel-Like Factor Family Members Contributing to the Self-Renewal of Mouse Embryonic Stem Cells and Cellular Reprogramming.
abstract: Pluripotency is maintained in mouse embryonic stem (ES) cells and is induced from somatic cells by the activation of appropriate transcriptional regulatory networks. Krüppel-like factor gene family members, such as Klf2, Klf4 and Klf5, have important roles in maintaining the undifferentiated state of mouse ES cells as well as in cellular reprogramming, yet it is not known whether other Klf family members exert self-renewal and reprogramming functions when overexpressed. In this study, we examined whether overexpression of any representative Klf family member, such as Klf1-Klf10, would be sufficient for the self-renewal of mouse ES cells. We found that only Klf2, Klf4, and Klf5 produced leukemia inhibitory factor (LIF)-independent self-renewal, although most KLF proteins, if not all, have the ability to occupy the regulatory regions of Nanog, a critical Klf target gene. We also examined whether overexpression of any of Klf1-Klf10 would be sufficient to convert epiblast stem cells into a naïve pluripotent state and found that Klf5 had such reprogramming ability, in addition to Klf2 and Klf4. We also delineated the functional domains of the Klf2 protein for LIF-independent self-renewal and reprogramming. Interestingly, we found that both the N-terminal transcriptional activation and C-terminal zinc finger domains were indispensable for this activity. Taken together, our comprehensive analysis provides new insight into the contribution of Klf family members to mouse ES self-renewal and cellular reprogramming.
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Hyojung
authors.initials: H
authors.lastname: Jeon
authors.affiliation: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Waku
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Azami
authors.affiliation: Department of Anatomy and Embryology, Human Biology Program, School of Integrative and Global Majors, University of Tsukuba, 1-1-1 Tennodai, Ibaraki, 305-8575, Japan.
authors.forename: Le Tran Phuc
authors.initials: le TP
authors.lastname: Khoa
authors.affiliation: Graduate School of Life and Environmental Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.|Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yanagisawa
authors.affiliation: Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8577, Japan.|International Institute for Integrative Sleep Medicine, Life Science Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.|Animal Resource Center, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8577, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan.|PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012, Japan.
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ema
mesh_terms: D000818:Animals; D000066673:Cell Self Renewal; D065150:Cellular Reprogramming; D002678:Chimera; D047369:Chromatin Immunoprecipitation; D000939:Epitopes / Q000378:metabolism; D005855:Germ Layers / Q000166:cytology; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D053605:Leukemia Inhibitory Factor / Q000378:metabolism; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology*; D005810:Multigene Family; D017434:Protein Structure, Tertiary
chemical_list: D000939:Epitopes; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D053605:Leukemia Inhibitory Factor