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Journal ArticleDOI

Role of the polycomb group proteins in hematopoietic stem cells.

01 Aug 2010-Development Growth & Differentiation (Dev Growth Differ)-Vol. 52, Iss: 6, pp 505-516
TL;DR: The role of PcG proteins in the epigenetic regulation of the self‐renewal capacity and multipotency of HSCs is focused on and epigenetics as a new field of H SC research is underscored.
Abstract: Polycomb group (PcG) proteins play a role in the transcriptional repression of genes through histone modifications. Recent studies have clearly demonstrated that PcG proteins are required for the maintenance of embryonic as well as a broad range of adult stem cells, including hematopoietic stem cells (HSCs). PcG proteins maintain the self-renewal capacity of HSCs by repressing tumor suppressor genes and keep differentiation programs poised for activation in HSCs by repressing a cohort of hematopoietic developmental regulator genes via bivalent chromatin domains. Enforced expression of one of the PcG genes, Bmi1, augments the self-renewal capacity of HSCs. PcG proteins also maintain redox homeostasis to prevent premature loss of HSCs. These findings established PcG proteins as essential regulators of HSCs and underscored epigenetics as a new field of HSC research. In this review, we focus on the role of PcG proteins in the epigenetic regulation of the self-renewal capacity and multipotency of HSCs.
Citations
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Journal ArticleDOI
08 Dec 2011-Blood
TL;DR: Several of the NUP98 fusion proteins have been shown to inhibit differentiation of hematopoietic precursors and to increase self-renewal of heMatopOietic stem or progenitor cells, providing a potential mechanism for malignant transformation.

253 citations

Journal ArticleDOI
TL;DR: Current literature on the relationship between the vigor of tissue stem cells and the process of aging is reviewed, with an emphasis on the rejuvenation of old tissues by the extrinsic modifications of stem cell niches.
Abstract: Aging is unmistakable and undeniable in mammals. Interestingly, mice develop cataracts, muscle atrophy, osteoporosis, obesity, diabetes and cognitive deficits after just 2–3 postnatal years, while it takes seven or more decades for the same age-specific phenotypes to develop in humans. Thus, chronological age corresponds differently with biological age in metazoan species and although many theories exist, we do not understand what controls the rate of mammalian aging. One interesting idea is that species-specific rate of aging represents a ratio of tissue attrition to tissue regeneration. Furthermore, current findings suggest that the age-imposed biochemical changes in the niches of tissue stem cells inhibit performance of this regenerative pool, which leads to the decline of tissue maintenance and repair. If true, slowing down stem cell and niche aging, thereby promoting tissue regeneration, could slow down the process of tissue and organismal aging. In this regard, recent studies of heterochronic parabi...

213 citations

Journal ArticleDOI
02 Aug 2012-Blood
TL;DR: It is suggested that Ezh2 inhibits differentiation programs in leukemic stem cells, thereby augmenting their leukemogenic activity.

181 citations

Journal ArticleDOI
TL;DR: Deletion of Ezh2 results in transcriptional repression of developmental regulator genes, derepression of oncogenic polycomb targets, and induction of MDS/MPN-like disease in mice that is exacerbated by concurrent deletion of Tet2.
Abstract: Polycomb group (PcG) proteins are essential regulators of hematopoietic stem cells. Recent extensive mutation analyses of the myeloid malignancies have revealed that inactivating somatic mutations in PcG genes such as EZH2 and ASXL1 occur frequently in patients with myelodysplastic disorders including myelodysplastic syndromes (MDSs) and MDS/myeloproliferative neoplasm (MPN) overlap disorders (MDS/MPN). In our patient cohort, EZH2 mutations were also found and often coincided with tet methylcytosine dioxygenase 2 (TET2) mutations. Consistent with these findings, deletion of Ezh2 alone was enough to induce MDS/MPN-like diseases in mice. Furthermore, concurrent depletion of Ezh2 and Tet2 established more advanced myelodysplasia and markedly accelerated the development of myelodysplastic disorders including both MDS and MDS/MPN. Comprehensive genome-wide analyses in hematopoietic progenitor cells revealed that upon deletion of Ezh2, key developmental regulator genes were kept transcriptionally repressed, suggesting compensation by Ezh1, whereas a cohort of oncogenic direct and indirect polycomb targets became derepressed. Our findings provide the first evidence of the tumor suppressor function of EZH2 in myeloid malignancies and highlight the cooperative effect of concurrent gene mutations in the pathogenesis of myelodysplastic disorders.

173 citations


Cites background from "Role of the polycomb group proteins..."

  • ...PcG genes have been implicated in the maintenance of self-renewing somatic and cancer stem cells (Konuma et al., 2010; Sauvageau and Sauvageau, 2010) and have typically been characterized as oncogenes, as exemplified by somatic activating mutations of EZH2 in follicular and diffuse large B cell…...

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References
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Journal ArticleDOI
TL;DR: Advances in the understanding of the mechanism and role of DNA methylation in biological processes are reviewed, showing that epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression.
Abstract: Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.

5,760 citations


"Role of the polycomb group proteins..." refers background in this paper

  • ...Epigenetic mechanisms involve DNA methylation, histone modifications, and regulation of chromatin structure (Jaenisch & Bird 2003), and play a key role in cellular memory, the ability of cells to remember through subsequent cell divisions their gene expression patterns that have been initiated by…...

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Journal ArticleDOI
21 Apr 2006-Cell
TL;DR: It is proposed that bivalent domains silence developmental genes in ES cells while keeping them poised for activation, highlighting the importance of DNA sequence in defining the initial epigenetic landscape and suggesting a novel chromatin-based mechanism for maintaining pluripotency.

5,131 citations


"Role of the polycomb group proteins..." refers background in this paper

  • ...Nonetheless, it remains controversial whether CBX proteins recruit PRC1 directly to H3K27me3-marked chromatin (Bernstein et al. 2006b; Ren et al. 2008)....

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  • ...…regulator gene promoters with bivalent domains consisting of overlapping repressive (H3K27me3) and activating (H3K4me3) histone modifications to keep developmental regulators ‘‘poised’’ for activation in ES cells (Bernstein et al. 2006a; Spivakov & Fisher 2007; Mendenhall & Bernstein 2008)....

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Journal ArticleDOI
29 Jun 2007-Cell
TL;DR: The transcriptional landscape of the four human HOX loci is characterized at five base pair resolution in 11 anatomic sites and 231 HOX ncRNAs are identified that extend known transcribed regions by more than 30 kilobases, suggesting transcription of ncRNA may demarcate chromosomal domains of gene silencing at a distance.

4,003 citations


"Role of the polycomb group proteins..." refers background in this paper

  • ...PcG proteins are classified into at least two functionally and biochemically distinct multimeric complexes, termed Polycomb repressive complexes (PRCs): an initiation complex, PRC2, and a maintenance complex, PRC1 (Table 1) (Sparmann & van Lohuizen 2006; Rajasekhar & Begemann 2007; Simon & Kingston 2009)....

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  • ...In this model, PRC2 is recruited to target gene promoters by accessory proteins, such as the sequence-specific DNA-binding protein YY1, and induces H3K27me3 marks....

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  • ...In contrast, PRC1 ion established by PRC2....

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  • ...In contrast, the H3K4me2 ⁄ 3-specific demethylases of JARID (Jumonjiand ARID-domain containing protein) subfamily has been identified to closely associate with PRC2 (Agger et al. 2008; Lan et al. 2008)....

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  • ...However, we do not know what happens in HSCs if the catalytic activity of either PRC1 or PRC2 is completely abolished....

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Journal ArticleDOI
18 May 2006-Nature
TL;DR: It is shown that PcG proteins directly repress a large cohort of developmental regulators in murine ES cells, the expression of which would otherwise promote differentiation, and dynamic repression of developmental pathways by Polycomb complexes may be required for maintaining ES cell pluripotency and plasticity during embryonic development.
Abstract: The mechanisms by which embryonic stem (ES) cells self-renew while maintaining the ability to differentiate into virtually all adult cell types are not well understood. Polycomb group (PcG) proteins are transcriptional repressors that help to maintain cellular identity during metazoan development by epigenetic modification of chromatin structure. PcG proteins have essential roles in early embryonic development and have been implicated in ES cell pluripotency, but few of their target genes are known in mammals. Here we show that PcG proteins directly repress a large cohort of developmental regulators in murine ES cells, the expression of which would otherwise promote differentiation. Using genome-wide location analysis in murine ES cells, we found that the Polycomb repressive complexes PRC1 and PRC2 co-occupied 512 genes, many of which encode transcription factors with important roles in development. All of the co-occupied genes contained modified nucleosomes (trimethylated Lys 27 on histone H3). Consistent with a causal role in gene silencing in ES cells, PcG target genes were de-repressed in cells deficient for the PRC2 component Eed, and were preferentially activated on induction of differentiation. Our results indicate that dynamic repression of developmental pathways by Polycomb complexes may be required for maintaining ES cell pluripotency and plasticity during embryonic development.

2,549 citations