Pasini D, Bracken AP, Jensen MR et al.Suz12 is essential for mouse development and for EZH2 histone methyltransferase activity. EMBO J 23:4061-4071

European Institute of Oncology, Milan, Italy.
The EMBO Journal (Impact Factor: 10.43). 11/2004; 23(20):4061-71. DOI: 10.1038/sj.emboj.7600402
Source: PubMed

ABSTRACT

SUZ12 is a recently identified Polycomb group (PcG) protein, which together with EZH2 and EED forms different Polycomb repressive complexes (PRC2/3). These complexes contain histone H3 lysine (K) 27/9 and histone H1 K26 methyltransferase activity specified by the EZH2 SET domain. Here we show that mice lacking Suz12, like Ezh2 and Eed mutant mice, are not viable and die during early postimplantation stages displaying severe developmental and proliferative defects. Consistent with this, we demonstrate that SUZ12 is required for proliferation of cells in tissue culture. Furthermore, we demonstrate that SUZ12 is essential for the activity and stability of the PRC2/3 complexes in mouse embryos, in tissue culture cells and in vitro. Strikingly, Suz12-deficient embryos show a specific loss of di- and trimethylated H3K27, demonstrating that Suz12 is indeed essential for EZH2 activity in vivo. In conclusion, our data demonstrate an essential role of SUZ12 in regulating the activity of the PRC2/3 complexes, which are required for regulating proliferation and embryogenesis.

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    • "Interestingly, knockdown of any single PRC2 component produced similar phenotypes, suggesting that all three proteins need to be present for normal PRC2 activity. This result was consistent with previous reports that all three core proteins are required for functional assembly of PRC2 (Cao and Zhang, 2004; Pasini et al., 2004; Montgomery et al., 2005). Based on this observation, we focused on EZH2 only in the subsequent studies. "
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    ABSTRACT: Neural crest cells arise from the border of the neural plate and epidermal ectoderm, migrate extensively and differentiate into diverse cell types during vertebrate embryogenesis. Although much has been learnt about growth factor signals and gene regulatory networks that regulate neural crest development, limited information is available on how epigenetic mechanisms control this process. In this study, we show that Polycomb repressive complex 2 (PRC2) cooperates with the transcription factor Snail2/Slug to modulate neural crest development in Xenopus. The PRC2 core components Eed, Ezh2 and Suz12 are expressed in the neural crest cells and are required for neural crest marker expression. Knockdown of Ezh2, the catalytic subunit of PRC2 for histone H3K27 methylation, results in defects in neural crest specification, migration and craniofacial cartilage formation. EZH2 interacts directly with Snail2, and Snail2 fails to expand the neural crest domains in the absence of Ezh2. Chromatin immunoprecipitation analysis shows that Snail2 regulates EZH2 occupancy and histone H3K27 trimethylation levels at the promoter region of the Snail2 target E-cadherin. Our results indicate that Snail2 cooperates with EZH2 and PRC2 to control expression of the genes important for neural crest specification and migration during neural crest development. © 2015. Published by The Company of Biologists Ltd.
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    • "RING1A, RING1B, and BMI1 are core PRC1 members while SUZ12, EZH2, and EED form core PRC2 members (de Napoles et al., 2004; Surface et al., 2010). Knockout studies of PcG proteins have established their importance during in vivo development (Voncken et al., 2003; Pasini et al., 2004) but their role in lineage specification and differentiation in vitro remains to be completely elucidated. Most studies have shown localization of PcG mediated histone modification (H3K27me3) during differentiation in mouse ES cells (Boyer et al., 2006; Lee et al., 2006; Pasini et al., 2007), while some have shown histone modifications catalyzed by PcG proteins during differentiation into a specific lineage (Hawkins et al., 2010; Xie et al., 2013). "
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    ABSTRACT: Human embryonic (hES) stem cells are excellent model to study lineage specification and differentiation into various cell types. Differentiation necessitates repression of specific genes not required for a particular lineage. Polycomb Group (PcG) proteins are key histone modifiers, whose primary function is gene repression. PcG proteins form complexes called Polycomb Repressive Complexes (PRCs), which catalyze histone modifications such as H2AK119ub1, H3K27me3 and H3K9me3. PcG proteins play a crucial role during differentiation of stem cells. The expression of PcG transcripts during differentiation of hES cells into endoderm, mesoderm and ectoderm lineage is yet to be shown. In-house derived hES cell line KIND1 was differentiated into endoderm, mesoderm and ectoderm lineages; followed by characterized using RT-PCR for HNF4A, CDX2, MEF2C, TBX5, SOX1 and MAP2. qRT-PCR and western blotting was performed to compare expression of PcG transcripts and proteins across all the three lineages. We observed that cells differentiated into endoderm showed upregulation of RING1B, BMI1, EZH2 and EED transcripts. Mesoderm differentiation was characterized by significant downregulation of all PcG transcripts during later stages. BMI1 and RING1B were upregulated while EZH2, SUZ12 and EED remained low during ectoderm differentiation. Western Blotting also showed distinct expression of BMI1 and EZH2 during differentiation into three germ layers. Our study shows that hES cells differentiating into endoderm, mesoderm and ectoderm lineages show distinct PcG expression profile at transcript and protein level. This article is protected by copyright. All rights reserved.
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    • "Suz12 À/À ES cells show severe differentiation defects (Pasini et al. 2007) and also Eed À/À and Ezh2 À/À ES cells display defects in lineage commitment (Shen et al. 2008). Finally, Suz12 À/À embryos, as Ezh2 À/À , and Eed À/À embryos are unable to undergo further development after implantation (Pasini et al. 2004), which suggests that PRC2 proteins are fundamental for developmental differentiation processes. Loss of single PRC components usually leads to slightly increased expression levels of lineage-specific genes and spontaneous differentiation at low levels (Pasini et al. 2007; Chamberlain et al. 2008). "
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    ABSTRACT: Lineage-specific phenotypes are the result of characteristic cellular gene expression patterns. Several epigenetic mechanisms have evolved that control the generation of these different phenotypes from the same genotype. Stem cells, in order to prevent differentiation, need to repress lineage-specific transcription factors and maintain the activity of stemness genes that promote self-renewal and pluripotency. In this context differentiation is basically a process governed by changes in gene activity during development that alter the stemness-specific epigenome towards lineage-specific patterns, often in response to transient factors or environmental stimuli. Sophisticated networks of protein complexes maintain epigenomic states in stem cells and determined cells after lineage decision and ensure their transmission through cell division. In addition, they are also essential for the epigenetic changes happening during differentiation induction that are crucial for lineage specification. The Polycomb group of genes codes for a variety of proteins that maintain repressive chromatin states. They are part of a complex cellular memory system that creates a layer of epigenetic information on top of the DNA sequence that ensures the maintenance and transmission of cell-specific expression patterns.
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