Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression

Takeshi Ueda, Yuichiro Nakata, Akiko Nagamachi, Norimasa Yamasaki, Akinori Kanai, Yasuyuki Sera, Masato Sasaki, Hirotaka Matsui, Zen Ichiro Honda, Hideaki Oda, Linda Wolff, Toshiya Inaba, Hiroaki Honda

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10370-10375
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number37
DOIs
StatePublished - Sep 13 2016
Externally publishedYes

Keywords

  • Hematologic malignancies
  • Histone methylation
  • Repressive histone marks

ASJC Scopus subject areas

  • General

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