PUBLICATION

Dominant-negative C/ebpalpha and polycomb group protein Bmi1 extends short-lived hematopoietic stem/progenitor cells lifespan and induces lethal dyserythropoiesis

Authors
Zhou, T., Wang, L., Zhu, K.Y., Dong, M., Xu, P.F., Chen, Y., Chen, S.J., Chen, Z., Deng, M., and Liu, T.X.
ID
ZDB-PUB-110811-32
Date
2011
Source
Blood   118(14): 3842-52 (Journal)
Registered Authors
Chen, Yi, Chen, Zhu, Deng, Min, Dong, Mei, Liu, Ting Xi, Xu, Peng-Fei, Zhu, Kang-Yong
Keywords
none
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • CCAAT-Enhancer-Binding Protein-alpha/genetics*
  • CCAAT-Enhancer-Binding Protein-alpha/metabolism
  • Cell Proliferation
  • Cell Survival
  • Cells, Cultured
  • Embryo, Nonmammalian/abnormalities
  • Embryo, Nonmammalian/blood supply
  • Erythropoiesis*
  • Gene Expression Regulation, Developmental*
  • Hematopoietic Stem Cells/cytology*
  • Hematopoietic Stem Cells/metabolism
  • Hematopoietic System/embryology*
  • Hematopoietic System/metabolism
  • Nuclear Proteins/genetics*
  • Nuclear Proteins/metabolism
  • Polycomb Repressive Complex 1
  • Zebrafish/embryology*
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
PubMed
21828130 Full text @ Blood
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.

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