The epigenetic basis for embryonic stem cell pluripotency

Szutorisz, Henrietta; Dillon, Niall

doi:10.1002/bies.20330

Cited by 53 publications

(35 citation statements)

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“…This signal may be a change in the activity of a specific transcription factor (activator or repressor) or other specific epigenetic changes different from the histone acetylation studied here. Possible epigenetic changes would include other histone tail modifications, substitutions of histone variants into nucleosomes, and DNA methylation at either a local or global level (8,36,(37)(38)(39). Recent work has identified the presence of a chromatin domain with bivalent epigenetic marks in the regulatory regions of a large set of developmental genes in mES cells (11).…”

Section: Discussionmentioning

confidence: 99%

The Role of Histone Acetylation in Regulating Early Gene Expression Patterns during Early Embryonic Stem Cell Differentiation

McCool

Singer

et al. 2007

Journal of Biological Chemistry

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We have examined the role of histone acetylation in the very earliest steps of differentiation of mouse embryonic stem cells in response to withdrawal of leukemia inhibitory factor (LIF) as a differentiation signal. The cells undergo dramatic changes in morphology and an ordered program of gene expression changes representing differentiation to all three germ layers over the first 3-5 days of LIF withdrawal. We observed a global increase in acetylation on histone H4 and to a lesser extent on histone H3 over this time period. Treatment of the cells with trichostatin A (TSA), a histone deacetylase inhibitor, induced changes in morphology, gene expression, and histone acetylation that mimicked differentiation induced by withdrawal of LIF. We examined localized histone acetylation in the regulatory regions of genes that were transcriptionally either active in undifferentiated cells, induced during differentiation, or inactive under all treatments. There was striking concordance in the histone acetylation patterns of specific genes induced by both TSA and LIF withdrawal. Increased histone acetylation in local regions correlated best with induction of gene expression. Finally, TSA treatment did not support the maintenance or progression of differentiation. Upon removal of TSA, the cells reverted to the undifferentiated phenotype. We concluded that increased histone acetylation at specific genes played a role in their expression, but additional events are required for maintenance of differentiated gene expression and loss of the pluripotent state.

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Section: Discussionmentioning

confidence: 99%

The Role of Histone Acetylation in Regulating Early Gene Expression Patterns during Early Embryonic Stem Cell Differentiation

McCool

Singer

et al. 2007

Journal of Biological Chemistry

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“…The differentiation and lineage commitment of stem cells are accompanied and determined by chromatin remodeling and establishment of epigenetic marks (Szutorisz and Dillon, 2005). The process of differentiation involves switching on or off genes that are expressed in specific types of cells and at specific times.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional Silencing of a Novel hTERT Reporter Locus during In Vitro Differentiation of Mouse Embryonic Stem Cells

Wang

Zhu

2007

MBoC

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The human telomerase reverse transcriptase hTERT is highly expressed in undifferentiated embryonic cells and silenced in the majority of somatic cells. To investigate the mechanisms of hTERT silencing, we have developed a novel reporter using a bacterial artificial chromosome (BAC) that contained the entire hTERT gene and its neighboring loci, hCRR9 and hXtrp2. Firefly and Renilla luciferases were used to monitor transcription from the hTERT and hCRR9 promoters, respectively. In mouse embryonic stem cells stably integrated with the BAC reporter, both hTERT and hCRR9 promoters were highly expressed. Upon differentiation into embryoid bodies and further into mineral-producing osteogenic cells, the hTERT promoter activity decreased progressively, whereas the hCRR9 promoter remained highly active, both resembling their endogenous counterparts. In fully differentiated cells, the hTERT promoter was completely silenced and adopted a chromatin structure that was similar to its native counterpart in human cells. Inhibition of histone deacetylases led to the opening of the hTERT promoter and partially relieved repression, suggesting that histone deacetylation was necessary but not sufficient for hTERT silencing. Thus, our result demonstrated that developmental silencing of the human TERT locus could be recapitulated in a chromosomal position-independent manner during the differentiation of mouse embryonic stem cells. INTRODUCTIONThe differentiation and lineage commitment of stem cells are accompanied and determined by chromatin remodeling and establishment of epigenetic marks (Szutorisz and Dillon, 2005). The process of differentiation involves switching on or off genes that are expressed in specific types of cells and at specific times. This programming of gene transcription occurs in the context of their native chromatin environment and is often stably maintained throughout the life span of an organism. Many genes essential for proper development of the embryo have been discovered and most of them encode proteins that regulate transcription (Arney and Fisher, 2004;Chambers and Smith, 2004). However, the dynamic interactions between these proteins and chromatin are still areas of intensive investigation. Detailed studies of gene transcription regulatory mechanisms during cell differentiation are essential not only for understanding the fundamental mechanisms of development and differentiation, but also for harnessing the differentiation and proliferation capacity that make stem cells invaluable for regenerative medicine.Telomerase, an enzyme synthesizing TTAGGG telomere repeats, is pertinent to self-renewal potential of stem cells and is required for long-term cellular proliferation and survival (Morrison et al., 1996;Lee et al., 1998). Telomerase is tightly regulated throughout development (Kim et al., 1994;Prowse and Greider, 1995). In early embryonic tissues and stem cells, telomerase is highly expressed and telomeres are stably maintained (Wright et al., 1996;Sharpless and DePinho, 2004). Although telomerase is detec...

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“…Moreover, half of these bivalent domains contain target sites that are common to Oct3/4, Sox2 and Nanog, as identified by genome-wide ChIP-on-Chip analysis (Boyer et al, 2005). Thus, these domains might signify the chromatin structure of genes that are in a differentiation-ready state, as proposed in the 'Localised Marking Model' by Szutoristz and Dillon (Szutoristz and Dillon, 2005). According to this model, most tissue-specific genes in ES cells would be targets for sequence-specific factors that can recruit histone-modifying enzymes, resulting in the formation of early transcription competence marks (ETCMs), which are enriched for histone H3 and H4 acetylation (H3Ac and H4Ac, respectively), and H3K4me3, all of which are histone marks associated with transcriptionally active regions.…”

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confidence: 99%

How is pluripotency determined and maintained?

2007

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Mouse embryonic stem (ES) cells are pluripotent, as they have the ability to differentiate into the various cell types of a vertebrate embryo. Pluripotency is a property of the inner cell mass (ICM), from which mouse ES cells are derived, and of the epiblast of the blastocyst. Recent extensive molecular studies of mouse ES cells have revealed the unique molecular mechanisms that govern pluripotency. These studies show that ES cells continue to self-renew because of a self-organizing network of transcription factors that prevents their differentiation and promotes their proliferation, and because of epigenetic processes that might be under the control of the pluripotent transcription factor network. IntroductionMouse embryonic stem (ES) cells, and the cells of the embryonic inner cell mass (ICM) from which mouse ES cells are derived, are pluripotent. According to recent consensus, pluripotency describes a cell's ability to give rise to all of the cells of an embryo and adult (Solter, 2006). Studies over the past few years have revealed the role that transcription factor networks and epigenetic processes play in the maintenance of ES cell pluripotency (Niwa et al., 2000;Mitsui et al., 2003;Chambers et al., 2003;Boyer et al., 2005;Niwa et al., 2005;Boyer et al., 2006). Among the findings to have emerged from these studies is that the functions of these transcription factors depend on the stage of development of a pluripotent cell, indicating that these factors function in combination with other processes (Sieweke and Graf, 1998). The activity of these transcription factors also depends on the accessibility of their target genes, which are made more or less accessible by the modification of their DNA, histones, or chromatin structure (Jaenisch and Bird, 2003). In this review, I discuss new insights into how transcription factor networks maintain mouse ES cell pluripotency and how these factors interface with epigenetic processes to control the pluripotency and differentiation of mouse ES cells. An overview of mouse ES cell derivation, proliferation and differentiation Pluripotent embryonic lineages and ES cell derivationMouse ES cells are derived mainly from the ICM of the mouse blastocyst (Evans and Kaufman, 1981;Martin, 1981) (see Fig. 1). As the embryo develops, the ICM gives rise to two distinct cell lineages: the extraembryonic endoderm, which goes on to form the extraembryonic tissues; and the epiblast, which gives rise to the primitive ectoderm at the egg-cylinder stage of embryogenesis, from which the embryo proper arises. The primitive ectoderm is distinct from the ICM in several ways. It cannot give rise to the trophectoderm, nor to the primitive endoderm (see Fig. 1); it also has an epithelial morphology distinct from that of the ICM (Gardner and Rossant, 1979). Importantly, the primitive ectoderm is the only cell lineage in which pluripotency is maintained at this stage of development, enabling it to give rise to all three embryonic germ layers and to primordial germ cells (see Fig. 1). However, as it la...

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The epigenetic basis for embryonic stem cell pluripotency

Cited by 53 publications

References 32 publications

The Role of Histone Acetylation in Regulating Early Gene Expression Patterns during Early Embryonic Stem Cell Differentiation

The Role of Histone Acetylation in Regulating Early Gene Expression Patterns during Early Embryonic Stem Cell Differentiation

Transcriptional Silencing of a Novel hTERT Reporter Locus during In Vitro Differentiation of Mouse Embryonic Stem Cells

How is pluripotency determined and maintained?

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