title: Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression.
abstract: Polycomb repressive complex 2 (PRC2) catalyzes the monomethylation, dimethylation, and trimethylation of histone H3 Lys27 (H3K27) and acts as a central epigenetic regulator that marks the repressive chromatin domain. Embryonic ectoderm development (EED), an essential component of PRC2, interacts with trimethylated H3K27 (H3K27me3) through the aromatic cage structure composed of its three aromatic amino acids, Phe97, Trp364, and Tyr365. This interaction allosterically activates the histone methyltransferase activity of PRC2 and thereby propagates repressive histone marks. In this study, we report the analysis of knock-in mice harboring the myeloid disorder-associated EED Ile363Met (I363M) mutation, analogous to the EED aromatic cage mutants. The I363M homozygotes displayed a remarkable and preferential reduction of H3K27me3 and died at midgestation. The heterozygotes increased the clonogenic capacity and bone marrow repopulating activity of hematopoietic stem/progenitor cells (HSPCs) and were susceptible to leukemia. Lgals3, a PRC2 target gene encoding a multifunctional galactose-binding lectin, was derepressed in I363M heterozygotes, which enhanced the stemness of HSPCs. Thus, our work provides in vivo evidence that the structural integrity of EED to H3K27me3 propagation is critical, especially for embryonic development and hematopoietic homeostasis, and that its perturbation increases the predisposition to hematologic malignancies.
authors: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan; takeshiueda@med.kindai.ac.jp hhonda@hiroshima-u.ac.jp.
authors: Takeshi
authors: T
authors: Ueda
authors: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
authors: Yuichiro
authors: Y
authors: Nakata
authors: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
authors: Akiko
authors: A
authors: Nagamachi
authors: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
authors: Norimasa
authors: N
authors: Yamasaki
authors: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
authors: Akinori
authors: A
authors: Kanai
authors: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
authors: Yasuyuki
authors: Y
authors: Sera
authors: Division of Infection and Host Defense, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan;
authors: Masato
authors: M
authors: Sasaki
authors: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
authors: Hirotaka
authors: H
authors: Matsui
authors: Health Care Center and Graduate School of Humanities and Sciences, Institute of Environmental Science for Human Life, Ochanomizu University, Tokyo 112-8611, Japan;
authors: Zen-Ichiro
authors: Z
authors: Honda
authors: Department of Pathology, Tokyo Women's Medical University, Tokyo 162-8666, Japan;
authors: Hideaki
authors: H
authors: Oda
authors: Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors: Linda
authors: L
authors: Wolff
authors: Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan;
authors: Toshiya
authors: T
authors: Inaba
authors: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan; takeshiueda@med.kindai.ac.jp hhonda@hiroshima-u.ac.jp.
authors: Hiroaki
authors: H
authors: Honda
mesh_terms: D000818:Animals; D047108:Embryonic Development / Q000235:genetics; D044127:Epigenesis, Genetic / Q000235:genetics; D037502:Galectin 3 / Q000737:chemistry / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006412:Hematopoietic Stem Cells / Q000737:chemistry / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000737:chemistry / Q000235:genetics; D006801:Humans; D007938:Leukemia / Q000235:genetics*; D051379:Mice; D063151:Polycomb Repressive Complex 2 / Q000737:chemistry* / Q000235:genetics
chemical_list: C107275:Eed protein, mouse; D037502:Galectin 3; C485095:Lgals3 protein, mouse; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2
keywords: hematologic malignancies; histone methylation; repressive histone marks