Dependency on the polycomb gene Ezh2 distinguishes fetal from adult hematopoietic stem cells

Polycomb-group (PcG) proteins are essential regulators of hematopoietic stem cells (HSCs). In contrast to Bmi1, a component of Polycomb repressive complex 1 (PRC1), the role of PRC2 and its components in hematopoiesis remains elusive. Here we show that Ezh2, a core component of PRC2, is essential fo...

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Bibliographic Details
Published in:Blood 2011-12, Vol.118 (25), p.6553-6561
Main Authors: Mochizuki-Kashio, Makiko, Mishima, Yuta, Miyagi, Satoru, Negishi, Masamitsu, Saraya, Atsunori, Konuma, Takaaki, Shinga, Jun, Koseki, Haruhiko, Iwama, Atsushi
Format: Article
Language:English
Subjects:
Adult Stem Cells - metabolism
Animals
Biological and medical sciences
Blotting, Western
Bone Marrow - metabolism
Bone Marrow Transplantation
Cells, Cultured
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Embryo, Mammalian - cytology
Embryo, Mammalian - embryology
Embryo, Mammalian - metabolism
Enhancer of Zeste Homolog 2 Protein
Female
Fetal Stem Cells - metabolism
Gene Expression Profiling
Hematologic and hematopoietic diseases
Hematopoiesis - genetics
Hematopoietic Stem Cells - metabolism
Histone-Lysine N-Methyltransferase - genetics
Histone-Lysine N-Methyltransferase - metabolism
Histones - metabolism
Liver - cytology
Liver - embryology
Liver - metabolism
Male
Medical sciences
Methylation
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Polycomb Repressive Complex 2
Polycomb-Group Proteins
Repressor Proteins - genetics
Repressor Proteins - metabolism
Reverse Transcriptase Polymerase Chain Reaction
Time Factors
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary:Polycomb-group (PcG) proteins are essential regulators of hematopoietic stem cells (HSCs). In contrast to Bmi1, a component of Polycomb repressive complex 1 (PRC1), the role of PRC2 and its components in hematopoiesis remains elusive. Here we show that Ezh2, a core component of PRC2, is essential for fetal, but not adult, HSCs. Ezh2-deficient embryos died of anemia because of insufficient expansion of HSCs/progenitor cells and defective erythropoiesis in fetal liver. Deletion of Ezh2 in adult BM, however, did not significantly compromise hematopoiesis, except for lymphopoiesis. Of note, Ezh2-deficient fetal liver cells showed a drastic reduction in trimethylation of histone H3 at lysine 27 (H3K27me3) accompanied by derepression of a large cohort of genes, whereas on homing to BM, they acquired a high level of H3K27me3 and long-term repopulating capacity. Quantitative RT-PCR revealed that Ezh1, the gene encoding a backup enzyme, is highly expressed in HSCs/progenitor cells in BM compared with those in fetal liver, whereas Ezh2 is ubiquitously expressed. These findings suggest that Ezh1 complements Ezh2 in the BM, but not in the fetal liver, and reveal that the reinforcement of PcG-mediated gene silencing occurs during the transition from proliferative fetal HSCs to quiescent adult HSCs.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2011-03-340554