Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells

Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
Cell (Impact Factor: 32.24). 05/2006; 125(2):301-13. DOI: 10.1016/j.cell.2006.02.043
Source: PubMed

ABSTRACT Polycomb group proteins are essential for early development in metazoans, but their contributions to human development are not well understood. We have mapped the Polycomb Repressive Complex 2 (PRC2) subunit SUZ12 across the entire nonrepeat portion of the genome in human embryonic stem (ES) cells. We found that SUZ12 is distributed across large portions of over two hundred genes encoding key developmental regulators. These genes are occupied by nucleosomes trimethylated at histone H3K27, are transcriptionally repressed, and contain some of the most highly conserved noncoding elements in the genome. We found that PRC2 target genes are preferentially activated during ES cell differentiation and that the ES cell regulators OCT4, SOX2, and NANOG cooccupy a significant subset of these genes. These results indicate that PRC2 occupies a special set of developmental genes in ES cells that must be repressed to maintain pluripotency and that are poised for activation during ES cell differentiation.

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    • "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). To the best of our knowledge present study for the first time in literature, describes the differential expression pattern of PcG transcripts and proteins during differentiation of hES cells into all three germ lineages. "
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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.
    Cell Biology International 01/2015; 39(5). DOI:10.1002/cbin.10431 · 1.93 Impact Factor
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    • "However, these studies examined only a small portion of the entire TF interactome and, by experimental design, revealed only TF pairs in isolation without taking into account the large repertoire of protein interactions between TFs and other non-TF proteins. Alternative approaches for exploring the TF interactome include interaction predictions based on coexpression (Adryan and Teichmann, 2010; Suzuki et al., 2009; Tomancak et al., 2007) and combined multiple-TF-occupancy studies (Cole et al., 2008; Lee et al., 2006; Mathur et al., 2008; Roy et al., 2010). In each case, direct interactions must still be confirmed through additional experimental means. "
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    ABSTRACT: Highlights: Direct physical interactions for the majority of Drosophila TFs are analyzed TF protein interactions are integrated with existing genomic data sets A resource for studying the biology of transcription factors is provided TF interactions are used to functionally interrogate the master-mind signaling network In Brief In this study, Rhee et al. systematically identify protein interactions for Drosophila transcription factors using a co-affinity purification/mass spectrometry approach. These data are integrated with existing genomic data sets to probe aspects of the Notch signaling pathway, and they provide a rich resource for forming biological hypotheses.
    Cell Reports 09/2014; 8(6):1-13. DOI:10.1016/j.celrep.2014.08.038 · 8.36 Impact Factor
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    • "The stepwise development of pancreatic beta cells is regulated by cell signaling, transcription factors, and chromatin modifiers. As noted in the Introduction, abundant evidence demonstrates a general role for the Polycomb complexes (PRCs) in lineage commitment (Lee et al, 2006; Surface et al, 2010) in general, and in endoderm and pancreatic progenitor development in particular. In addition, Ezh2 is necessary in the adult to maintain the physiological function of beta cells (Chen et al, 2009). "
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    ABSTRACT: Endoderm cells undergo sequential fate choices to generate insulin-secreting beta cells. Ezh2 of the PRC2 complex, which generates H3K27me3, modulates the transition from endoderm to pancreas progenitors, but the role of Ezh2 and H3K27me3 in the next transition to endocrine progenitors is unknown. We isolated endoderm cells, pancreas progenitors, and endocrine progenitors from different staged mouse embryos and analyzed H3K27me3 genome-wide. Unlike the decline in H3K27me3 domains reported during embryonic stem cell differentiation in vitro, we find that H3K27me3 domains increase in number during endocrine progenitor development in vivo. Genes that lose the H3K27me3 mark typically encode transcriptional regulators, including those for pro-endocrine fates, whereas genes that acquire the mark typically are involved in cell biology and morphogenesis. Deletion of Ezh2 at the pancreas progenitor stage enhanced the production of endocrine progenitors and beta cells. Inhibition of EZH2 in embryonic pancreas explants and in human embryonic stem cell cultures increased endocrine progenitors in vitro. Our studies reveal distinct dynamics in H3K27me3 targets in vivo and a means to modulate beta cell development from stem cells.
    The EMBO Journal 08/2014; 33(19). DOI:10.15252/embj.201488671 · 10.43 Impact Factor
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