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

• Published in: Blood Vol. 118; no. 25; pp. 6553 - 6561
• Main Authors: Mochizuki-Kashio, Makiko, Mishima, Yuta, Miyagi, Satoru, Negishi, Masamitsu, Saraya, Atsunori, Konuma, Takaaki, Shinga, Jun, Koseki, Haruhiko, Iwama, Atsushi
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 15.12.2011; Americain Society of Hematology
• 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; Human; PcG gene; Fetal cell; Hematology; Stem cell; Hematopoietic cell; Ezh2 gene; Adult
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2011-03-340554

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.