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A bivalent chromatin structure marks key developmental genes in embryonic stem cells, Cell 125
, 2006
"... The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by ex ..."
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The most highly conserved noncoding elements (HCNEs) in mammalian genomes cluster within regions enriched for genes encoding developmentally important transcription factors (TFs). This suggests that HCNE-rich regions may contain key regulatory controls involved in development. We explored this by examining histone methylation in mouse embryonic stem (ES) cells across 56 large HCNE-rich loci. We identified a specific modification pattern, termed ‘‘bivalent domains,’ ’ consisting of large regions of H3 lysine 27 methylation harboring smaller regions of H3 lysine 4 methylation. Bivalent domains tend to coincide with TF genes expressed at low levels. We propose that bivalent domains silence developmental genes in ES cells while keeping them poised for activation. We also found striking correspondences between genome sequence and histone methylation in ES cells, which become notably weaker in differentiated cells. These results highlight the importance of DNA sequence in defining the initial epigenetic landscape and suggest a novel chromatin-based mechanism for maintaining pluripotency.
Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-Depleted Murine Embryonic Stem
"... Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenet ..."
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Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in a concordant expression
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"... expression of stemness genes or for induction of lineage-specificSzutorisz andDillon, 2005; Niwa, 2007). Prominent histonemodifi-cations include H3K4 methylation, implicated in transcriptional activation and deposited by Trithorax group proteins, and H3K27 esis but, for similar reasons, it is not kn ..."
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expression of stemness genes or for induction of lineage-specificSzutorisz andDillon, 2005; Niwa, 2007). Prominent histonemodifi-cations include H3K4 methylation, implicated in transcriptional activation and deposited by Trithorax group proteins, and H3K27 esis but, for similar reasons, it is not known if H3K4 methylation is directly involved (Ernst et al., 2004). There are no reports regarding ESCs deficient in MLL3, MLL4, or SET1. In contrast,methylation, implicated in transcriptional repression and depos-ited by Polycomb group proteins (reviewed in Kouzarides, 2007). depletion of any of the core subunits effectively reduces the global level of H3K4 methylation (Dou et al., 2006). However,a component of the bivalent mark, at developmental genes during the ESC fate transitions.
SPOTLIGHT REVIEW NO points to epigenetics in vascular development
"... Abstract Our understanding of epigenetic mechanisms important for embryonic vascular development and cardiovascular differentiation is still in its infancy. Although molecular analyses, including massive genome sequencing and/or in vitro/in vivo targeting of specific gene sets, has led to the identi ..."
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Abstract Our understanding of epigenetic mechanisms important for embryonic vascular development and cardiovascular differentiation is still in its infancy. Although molecular analyses, including massive genome sequencing and/or in vitro/in vivo targeting of specific gene sets, has led to the identification of multiple factors involved in stemness main-tenance or in the early processes of embryonic layers specification, very little is known about the epigenetic commit-ment to cardiovascular lineages. The object of this review will be to outline the state of the art in this field and trace the perspective therapeutic consequences of studies aimed at elucidating fundamental epigenetic networks. Special attention will be paid to the emerging role of nitric oxide in this field.
Cell Stem Cell Article Global Transcription in Pluripotent Embryonic Stem Cells
"... 8These authors contributed equally to this work. 9These authors contributed equally to this work as senior authors. ..."
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8These authors contributed equally to this work. 9These authors contributed equally to this work as senior authors.
12 Reviews on Recent Clinical Trials, 2009, 4, 12-26 Molecular Pathology of Sarcomas
"... Abstract: Bone and soft tissue sarcomas are an infrequent group of tumours with a prevalence of 4 in 100000 people/year. Sarcomas, such as synovial sarcoma, Ewing’s sarcoma and osteosarcoma, are more usual in adolescents or in young adults. Neoplasias such as leiomyosarcoma or liposarcoma are more f ..."
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Abstract: Bone and soft tissue sarcomas are an infrequent group of tumours with a prevalence of 4 in 100000 people/year. Sarcomas, such as synovial sarcoma, Ewing’s sarcoma and osteosarcoma, are more usual in adolescents or in young adults. Neoplasias such as leiomyosarcoma or liposarcoma are more frequent in patients over 55 years. One relevant topic is related to sarcomagenesis elucidation, a key for discovering the early molecular mechanisms involved in the development of sarcomas as well as the identification of reliable molecular markers and possible therapeutic targets. Today, it is known that the cellular context contributes to the phenotype. Analysis of gene expression profiling of human sarcomas revealed tightly clustered groups and could denote the existence of common signalling pathways for each branch. From the molecular point of view, these neoplasias are grouped into two main types: (a) sarcomas showing specific genetic alterations and relatively simple karyotypes, and translocations which originate gene fusions (e.g., EWS-FLI1 in Ewing’s sarcoma); or specific genetic mutations (e.g., c-kit in the gastrointestinal stromal tumour), and (b) sarcomas showing unspecific gene alterations and very complex karyotypes, and very numerous gains and losses. This review points out the clinical projection of sarcomagenesis elucidation and knowledge of diverse types of molecular alterations.
Review Article Glioma Revisited: From Neurogenesis and Cancer Stem Cells to the Epigenetic Regulation of the Niche
"... Copyright © 2012 Felipe de Almeida Sassi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gliomas are the most incident brain t ..."
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Copyright © 2012 Felipe de Almeida Sassi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Gliomas are the most incident brain tumor in adults. This malignancy has very low survival rates, even when combining radio-and chemotherapy. Among the gliomas, glioblastoma multiforme (GBM) is the most common and aggressive type, and patients frequently relapse or become refractory to conventional therapies. The fact that such an aggressive tumor can arise in such a carefully orchestrated organ, where cellular proliferation is barely needed to maintain its function, is a question that has intrigued scientists until very recently, when the discovery of the existence of proliferative cells in the brain overcame such challenges. Even so, the precise origin of gliomas still remains elusive. Thanks to new advents in molecular biology, researchers have been able to depict
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"... Title: WDR82, a key epigenetics related factor, plays crucial role in normal early embryonic development Short title: WDR82 is critical for embryo development Summary sentence: Wdr82 regulated gene expression during early embryo development through epigenetic modification and was lethal when defecte ..."
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Title: WDR82, a key epigenetics related factor, plays crucial role in normal early embryonic development Short title: WDR82 is critical for embryo development Summary sentence: Wdr82 regulated gene expression during early embryo development through epigenetic modification and was lethal when defected.
RESEARCH ARTICLE Markers of Pluripotency in Human Amniotic Epithelial Cells and Their Differentiation to Progenitor of Cortical Neurons
"... Human pluripotent stem cells (hPSC) have promise for regenerative medicine due to their auto-renovation and differentiation capacities. Nevertheless, there are several ethical and methodological issues about these cells that have not been resolved. Human amniotic epi-thelial cells (hAEC) have been p ..."
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Human pluripotent stem cells (hPSC) have promise for regenerative medicine due to their auto-renovation and differentiation capacities. Nevertheless, there are several ethical and methodological issues about these cells that have not been resolved. Human amniotic epi-thelial cells (hAEC) have been proposed as source of pluripotent stem cells. Several groups have studied hAEC but have reported inconsistencies about their pluripotency properties. The aim of the present study was the in vitro characterization of hAEC collected from a Mex-ican population in order to identify transcription factors involved in the pluripotency circuitry and to determine their epigenetic state. Finally, we evaluated if these cells differentiate to cortical progenitors. We analyzed qualitatively and quantitatively the expression of the tran-scription factors of pluripotency (OCT4, SOX2, NANOG, KLF4 and REX1) by RT-PCR and RT-qPCR in hAEC. Also, we determined the presence of OCT4, SOX2, NANOG, SSEA3, SSEA4, TRA-1-60, E-cadherin, KLF4, TFE3 as well as the proliferation and epigenetic state by immunocytochemistry of the cells. Finally, hAEC were differentiated towards cortical pro-genitors using a protocol of two stages. Here we show that hAEC, obtained from a Mexican
