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Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency
Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were identified in hematopoietic malignancies. To c...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949429/ https://www.ncbi.nlm.nih.gov/pubmed/27432459 http://dx.doi.org/10.1038/srep29454 |
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author | Ikeda, Kenichiro Ueda, Takeshi Yamasaki, Norimasa Nakata, Yuichiro Sera, Yasuyuki Nagamachi, Akiko Miyama, Takahiko Kobayashi, Hiroshi Takubo, Keiyo Kanai, Akinori Oda, Hideaki Wolff, Linda Honda, Zen-ichiro Ichinohe, Tatsuo Matsubara, Akio Suda, Toshio Inaba, Toshiya Honda, Hiroaki |
author_facet | Ikeda, Kenichiro Ueda, Takeshi Yamasaki, Norimasa Nakata, Yuichiro Sera, Yasuyuki Nagamachi, Akiko Miyama, Takahiko Kobayashi, Hiroshi Takubo, Keiyo Kanai, Akinori Oda, Hideaki Wolff, Linda Honda, Zen-ichiro Ichinohe, Tatsuo Matsubara, Akio Suda, Toshio Inaba, Toshiya Honda, Hiroaki |
author_sort | Ikeda, Kenichiro |
collection | PubMed |
description | Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were identified in hematopoietic malignancies. To clarify the role(s) of EED in adult hematopoiesis and leukemogenesis, we generated Eed conditional knockout (Eed(Δ/Δ)) mice. Eed(Δ/Δ) mice died in a short period with rapid decrease of hematopoietic cells. Hematopoietic stem/progenitor cells (HSPCs) were markedly decreased with impaired bone marrow (BM) repopulation ability. Cell cycle analysis of HSPCs demonstrated increased S-phase fraction coupled with suppressed G0/G1 entry. Genes encoding cell adhesion molecules are significantly enriched in Eed(Δ/Δ) HSPCs, and consistently, Eed(Δ/Δ) HSPCs exhibited increased attachment to a major extracellular matrix component, fibronectin. Thus, EED deficiency increases proliferation on one side but promotes quiescence possibly by enhanced adhesion to the hematopoietic niche on the other, and these conflicting events would lead to abnormal differentiation and functional defect of Eed(Δ/Δ) HSPCs. In addition, Eed haploinsufficiency induced hematopoietic dysplasia, and Eed heterozygous mice were susceptible to malignant transformation and developed leukemia in cooperation with Evi1 overexpression. Our results demonstrated differentiation stage-specific and dose-dependent roles of EED in normal hematopoiesis and leukemogenesis. |
format | Online Article Text |
id | pubmed-4949429 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-49494292016-07-26 Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency Ikeda, Kenichiro Ueda, Takeshi Yamasaki, Norimasa Nakata, Yuichiro Sera, Yasuyuki Nagamachi, Akiko Miyama, Takahiko Kobayashi, Hiroshi Takubo, Keiyo Kanai, Akinori Oda, Hideaki Wolff, Linda Honda, Zen-ichiro Ichinohe, Tatsuo Matsubara, Akio Suda, Toshio Inaba, Toshiya Honda, Hiroaki Sci Rep Article Polycomb repressive complex 2 (PRC2) participates in transcriptional repression through methylation of histone H3K27. The WD-repeat protein embryonic ectoderm development (EED) is a non-catalytic but an essential component of PRC2 and its mutations were identified in hematopoietic malignancies. To clarify the role(s) of EED in adult hematopoiesis and leukemogenesis, we generated Eed conditional knockout (Eed(Δ/Δ)) mice. Eed(Δ/Δ) mice died in a short period with rapid decrease of hematopoietic cells. Hematopoietic stem/progenitor cells (HSPCs) were markedly decreased with impaired bone marrow (BM) repopulation ability. Cell cycle analysis of HSPCs demonstrated increased S-phase fraction coupled with suppressed G0/G1 entry. Genes encoding cell adhesion molecules are significantly enriched in Eed(Δ/Δ) HSPCs, and consistently, Eed(Δ/Δ) HSPCs exhibited increased attachment to a major extracellular matrix component, fibronectin. Thus, EED deficiency increases proliferation on one side but promotes quiescence possibly by enhanced adhesion to the hematopoietic niche on the other, and these conflicting events would lead to abnormal differentiation and functional defect of Eed(Δ/Δ) HSPCs. In addition, Eed haploinsufficiency induced hematopoietic dysplasia, and Eed heterozygous mice were susceptible to malignant transformation and developed leukemia in cooperation with Evi1 overexpression. Our results demonstrated differentiation stage-specific and dose-dependent roles of EED in normal hematopoiesis and leukemogenesis. Nature Publishing Group 2016-07-19 /pmc/articles/PMC4949429/ /pubmed/27432459 http://dx.doi.org/10.1038/srep29454 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Ikeda, Kenichiro Ueda, Takeshi Yamasaki, Norimasa Nakata, Yuichiro Sera, Yasuyuki Nagamachi, Akiko Miyama, Takahiko Kobayashi, Hiroshi Takubo, Keiyo Kanai, Akinori Oda, Hideaki Wolff, Linda Honda, Zen-ichiro Ichinohe, Tatsuo Matsubara, Akio Suda, Toshio Inaba, Toshiya Honda, Hiroaki Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency |
title | Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency |
title_full | Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency |
title_fullStr | Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency |
title_full_unstemmed | Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency |
title_short | Maintenance of the functional integrity of mouse hematopoiesis by EED and promotion of leukemogenesis by EED haploinsufficiency |
title_sort | maintenance of the functional integrity of mouse hematopoiesis by eed and promotion of leukemogenesis by eed haploinsufficiency |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949429/ https://www.ncbi.nlm.nih.gov/pubmed/27432459 http://dx.doi.org/10.1038/srep29454 |
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