Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells

Lee, Tong Ihn; Jenner, Richard G.; Boyer, Laurie A.; Guenther, Matthew G.; Levine, Stuart S.; Kumar, R.; Chevalier, B.; Johnstone, Sarah E.; Cole, Megan F.; Isono, Kyoichi; Koseki, Haruhiko; Fuchikami, Takuya; Abe, Kuniya; Murray, Heather L.; Zucker, Jacob; Yuan, Bingbing; Bell, George W.; Herbolsheimer, Elizabeth; Hannett, Nancy M.; Sun, Kaiming; Odom, Duncan T.; Otte, Arie P.; Volkert, Thomas L.; Bartel, David P.; Melton, Douglas A.; Gifford, David K.; Jaenisch, Rudolf; Young, Richard A.

doi:10.1016/j.cell.2006.02.043

Cited by 2,046 publications

(2,181 citation statements)

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“…By contrast, Meis1 and Fli1, two genes that are normally repressed by PRC2 (Lee et al, 2006), were actively transcribed in all investigated t(4;11) biopsy probes. This may indicate that specific Nanog/Oct4 target genes may be deregulated in the presence of the t(4;11) fusion proteins.…”

Section: Discussionmentioning

confidence: 80%

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

et al. 2006

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The reciprocal chromosomal translocation t(4;11) is correlated with infant, childhood, adult and therapyrelated high-risk acute leukemia. Here, we investigated the biological effects of MLL . AF4, AF4 . MLL or the combination of both reciprocal fusion proteins in a conditional in vitro cell culture model system. Several parameters like cell growth, cell cycling capacity, apoptotic behavior and growth transformation were investigated under physiological and stress conditions. Co-transfected cells displayed the highest resistance against apoptotic triggers, cell cycling capacity and lossof-contact inhibition. These analyses were complemented by gene expression profiling experiments and specific gene signatures were established for each of the three cell lines. Interestingly, co-transfected cells strongly upregulate the homeobox gene Nanog. In combination with Oct4, the Nanog homeoprotein is steering maintenance of pluripotency and self-renewal in embryonic stem cells. Transcription of Nanog and other stem cell factors, like Oct4 and Bmi1, was verified in biopsy material of t(4;11) patient cells which express both reciprocal t(4;11) fusion genes. In conclusion, the presence of both reciprocal MLL fusion proteins confers biological properties known from t(4;11) leukemia, suggesting that each of the two fusion proteins contribute specific properties and, in combination, also synergistic effects to the leukemic phenotype.

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Section: Discussionmentioning

confidence: 80%

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

et al. 2006

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“…[19][20][21] Boyer et al reported the genes occupied by PRC1 (Phc1 and Rnf2) and PRC2 (Suz12 and Eed) in murine ESCs. 19 To explore a novel target of Bmi1 in hepatic stem/progenitor cells, we compared the list of down-regulated genes with the ChIP-on-chip data documented by Boyer et al 19 As a result, five genes namely, Sox17, Irx5, Gjb2, Shox2, and Bhmt2 in the present study appeared to be regulated by both PRC1 and/or PRC2 in ESCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

et al. 2010

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We previously reported that forced expression of Bmi1 (B lymphoma Moloney murine leukemia virus insertion region 1 homolog) in murine hepatic stem/progenitor cells purified from fetal liver enhances their self-renewal and drives cancer initiation. In the present study, we examined the contribution of the Ink4a/Arf tumor suppressor gene locus, one of the major targets of Bmi1, to stem cell expansion and cancer initiation. Bmi1 2/2 Deltalike protein (Dlk) 1 hepatic stem/progenitor cells showed de-repression of the Ink4a/Arf locus and displayed impaired growth activity. In contrast, Ink4a/Arf 2/2 Dlk 1 cells gave rise to considerably larger colonies containing a greater number of bipotent cells than wild-type Dlk 1 cells. Although Ink4a/Arf 2/2 Dlk 1 cells did not initiate tumors in recipient nonobese diabetic/severe combined immunodeficiency mice, enforced expression of Bmi1 in Ink4a/Arf 2/2 Dlk 1 cells further augmented their self-renewal capacity and resulted in tumor formation in vivo. Microarray analyses successfully identified five downregulated genes as candidate downstream targets for Bmi1 in hepatic stem/progenitor cells. Of these genes, enforced expression of sex determining region Y-box 17 (Sox17) in Dlk 1 cells strongly suppressed colony propagation and tumor growth. Conclusion: These results indicate that repression of targets of Bmi1 other than the Ink4a/Arf locus plays a crucial role in the oncogenic transformation of hepatic stem/progenitor cells. Functional analyses of Bmi1 target genes would be of importance to elucidate the molecular machinery underlying hepatic stem cell system and explore therapeutic approaches for the eradication of liver cancer stem cells.

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“…But our ChIP assay showed that siSnail, but not siYY1, dissociated the recruitment of EZH2, HDAC1/2 from this region. Several groups had reported that the PcG proteins and H3K27me3 were tend to be broadly distributed across many kilobases of target gene locus Lee et al, 2006;Schwartz et al, 2006;Simon and Kingston, 2009). An alternative interpretation is that the large distribution of PcG complex is account for the looping action mechanism, leading PcG complex to be crosslinked to more distant nucleosomes (Schwartz and Pirrotta, 2007;Tiwari et al, 2008).…”

Section: Ezh2 Promotes Npc Cell Aggressiveness Z-t Tong Et Almentioning

confidence: 99%

EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin

et al. 2011

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The enhancer of zeste homolog 2 (EZH2) is upregulated and has an oncogenic role in several types of human cancer. However, the abnormalities of EZH2 and its underlying mechanisms in the pathogenesis of nasopharyngeal carcinoma (NPC) remain unknown. In this study, we found that high expression of EZH2 in NPC was associated closely with an aggressive and/or poor prognostic phenotype (Po0.05). In NPC cell lines, knockdown of EZH2 by short hairpin RNA was sufficient to inhibit cell invasiveness/metastasis both in vitro and in vivo, whereas ectopic overexpression of EZH2 supported NPC cell invasive capacity with a decreased expression of E-cadherin. In addition, ablation of endogenous Snail in NPC cells virtually totally prevented the repressive activity of EZH2 to E-cadherin, indicating that Snail might be a predominant mediator of EZH2 to suppress E-cadherin. Furthermore, co-immunoprecipitation (IP), chromatin IP and luciferase reporter assays demonstrated that in NPC cells, (1) EZH2 interacted with HDAC1/HDAC2 and Snail to form a repressive complex; (2) these components interact in a linear fashion, not in a triangular fashion, that is, HDAC1 or HDAC2 bridge the interaction between EZH2 and Snail; and (3) the EZH2/HDAC1/2/Snail complex could closely bind to the E-cadherin promoter by Snail, but not YY1, to repress E-cadherin. The data provided in this report suggest a critical role of EZH2 in the control of cell invasion and/or metastasis by forming a co-repressor complex with HDAC1/HDAC2/Snail to repress E-cadherin, an activity that might be responsible, at least in part, for the development and/or progression of human NPCs.

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Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells

Cited by 2,046 publications

References 67 publications

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

Combined effects of the two reciprocal t(4;11) fusion proteins MLL·AF4 and AF4·MLL confer resistance to apoptosis, cell cycling capacity and growth transformation

Bmi1promotes hepatic stem cell expansion and tumorigenicity in bothInk4a/Arf-dependent and -independent manners in Mice

EZH2 supports nasopharyngeal carcinoma cell aggressiveness by forming a co-repressor complex with HDAC1/HDAC2 and Snail to inhibit E-cadherin

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