title: Uhrf1 controls the self-renewal versus differentiation of hematopoietic stem cells by epigenetically regulating the cell-division modes.
abstract: Hematopoietic stem cells (HSCs) are able to both self-renew and differentiate. However, how individual HSC makes the decision between self-renewal and differentiation remains largely unknown. Here we report that ablation of the key epigenetic regulator Uhrf1 in the hematopoietic system depletes the HSC pool, leading to hematopoietic failure and lethality. Uhrf1-deficient HSCs display normal survival and proliferation, yet undergo erythroid-biased differentiation at the expense of self-renewal capacity. Notably, Uhrf1 is required for the establishment of DNA methylation patterns of erythroid-specific genes during HSC division. The expression of these genes is enhanced in the absence of Uhrf1, which disrupts the HSC-division modes by promoting the symmetric differentiation and suppressing the symmetric self-renewal. Moreover, overexpression of one of the up-regulated genes, Gata1, in HSCs is sufficient to phenocopy Uhrf1-deficient HSCs, which show impaired HSC symmetric self-renewal and increased differentiation commitment. Taken together, our findings suggest that Uhrf1 controls the self-renewal versus differentiation of HSC through epigenetically regulating the cell-division modes, thus providing unique insights into the relationship among Uhrf1-mediated DNA methylation, cell-division mode, and HSC fate decision.
authors.affiliation: State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jingyao
authors.initials: J
authors.lastname: Zhao
authors.affiliation: State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xufeng
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
authors.forename: Guangrong
authors.initials: G
authors.lastname: Song
authors.affiliation: State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jiali
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Haifeng
authors.initials: H
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cell Biology, Chinese Academy of Sciences Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; liux@sibs.ac.cn.|School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Liu
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002454:Cell Differentiation / Q000502:physiology*; D000066673:Cell Self Renewal / Q000502:physiology*; D019175:DNA Methylation / Q000502:physiology*; D044127:Epigenesis, Genetic; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D009687:Nuclear Proteins; D044767:Ubiquitin-Protein Ligases; C117054:Uhrf1 protein, mouse
keywords: HSCs; Uhrf1; cell fate decision; cell-division mode; epigenetic regulation