title: Dominant-negative C/ebpα and polycomb group protein Bmi1 extend short-lived hematopoietic stem/progenitor cell life span and induce lethal dyserythropoiesis.
abstract: The primitive hematopoietic stem/progenitor cells (HSPCs) during embryonic hematopoiesis are thought to be short-lived (SL) with limited self-renewal potential. The fate and consequence of these short-lived HSPCs, once reprogrammed into "long-lived" in a living animal body, remain unknown. Here we show that targeted expression of a dominant-negative C/ebpα (C/ebpαDN) in the primitive SL-HSPCs during zebrafish embryogenesis extends their life span, allowing them to survive to later developmental stage to colonize the definitive hematopoietic sites, where they undergo a proliferative expansion followed by erythropoietic dysplasia and embryonic lethality because of circulation congestion. Mechanistically, C/ebpαDN binds to a conserved C/EBP-binding motif in the promoter region of bmi1 gene, associated with a specific induction of bmi1 transcription in the transgenic embryos expressing C/ebpαDN. Targeted expression of Bmi1 in the SL-HSPCs recapitulates nearly all aberrant phenotypes induced by C/ebpαDN, whereas knockdown of bmi1 largely rescues these abnormalities. The results indicate that Bmi1 acts immediately downstream of C/ebpαDN to regulate the survival and self-renewal of HSPCs and contribute to the erythropoietic dysplasia.
authors.affiliation: Key Laboratory of Stem Cell Biology and State Key Laboratory of Medical Genomics and Laboratory of Development and Diseases, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine, and Shanghai Institute of Hematology, RuiJin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Kang-Yong
authors.initials: KY
authors.lastname: Zhu
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.forename: Peng-Fei
authors.initials: PF
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Sai-Juan
authors.initials: SJ
authors.lastname: Chen
authors.forename: Zhu
authors.initials: Z
authors.lastname: Chen
authors.forename: Min
authors.initials: M
authors.lastname: Deng
authors.forename: Ting Xi
authors.initials: TX
authors.lastname: Liu
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000098:blood supply; D004920:Erythropoiesis; D018507:Gene Expression Regulation, Developmental; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D006413:Hematopoietic System / Q000196:embryology* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D009687:Nuclear Proteins; D029961:Zebrafish Proteins; C459595:bmi1a protein, zebrafish; D063150:Polycomb Repressive Complex 1