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.histone methylation | repressive histone marks | hematologic malignancies

PRC2 is high maintenance

“…13A), deletions, amplifications, and translocations in chromatin-modifying enzymes, including those in different subunits of PRC2 are found in various types of human cancer. For example, nonsense and inactivating mutations in EED or SUZ12 are found in 70%-90% of malignant peripheral nerve sheath tumors (MPNSTs); in EZH2, EED, or SUZ12 in 25% of T-cell acute lymphoblastic leukemia (T-ALL) (Ntziachristos et al 2012;Lee et al 2014); and in PRC2 core subunits in other cancer types with lower frequencies, such as myelodysplastic syndrome (MDS) and other myeloid malignancies (Sashida et al 2014;Ueda et al 2016). Although the functions of many other sense mutations in core PRC2 subunits remain undetermined, most of them are likely to be loss of function, as mutations tend to be deleterious rather than to evolve new functions.…”

“…However, most evidence relies on EZH2 immunoprecipitation results, and it remains unclear whether such interactions are actually stable or Major groups of mutations that influence PRC2 function in cancer. Mutations that are found in the EED cage (EED I363M) (Ueda et al 2016) and SRM domain of EZH2 (P132S, D142V, and F145L) inhibit allosteric activation of PRC2 (Lee et al 2018c). Mutations that are found in the catalytic SET domain (Y646X [X = S, N, F, C, or H], A682G, A682V, and A692V) are gain-of-function "kinetic" mutations.…”

Acquired expression of CblQ367P in mice induces dysplastic myelopoiesis mimicking chronic myelomonocytic leukemia

“…[24][25][26][27] Among the integration sites detected, we identified 3 common integration sites (CISs): Mecom (Mds1 and Evi1 complex locus, also known as Evi1, ecotropic virus integration site 1), 28 Sfpi-1 (spleen focus forming virus proviral integration oncogene, also known as PU.1), 29 and Rassf2 (Ras association [RalGDS/AF-6] domain family member 2) 30 (supplemental Table 2). Examination of the expressional alteration of these genes in Cbl Q367P 1 MOL4070A and Cbl Q367P 1 ENU tumor tissues revealed that, although the expression levels of Rassf2 and Sfpi-1 were not apparently increased, that of Mecom/Evi1 was upregulated more than fivefold in 3 tumors (no.…”

Roles of Polycomb gene EED in pathogenesis and prognosis of acute myeloid leukemia and diffuse large B cell lymphoma

“…It seems that lower EED mRNA level could increase the metastasis and invasion potential of APL cancer cells. Viewed together with this hypothesis, we found that haploinsufficiency of EED gene in mouse caused by conditional deletion or mutant knockin could also increase the metastasis and invasion risk of leukemia cells (Ikeda et al 2016;Ueda et al 2016).…”