Epigenetic programming and reprogramming during development
TL;DR: Current models of epigenetic erasure are summarized, the various enzymes and mechanisms that may operate in cellular reprogramming are discussed, and some of the recent advances in understanding how epigenetic remodeling contributes to conversion of cell fate are reviewed.
Abstract: Cell identity is determined by specific gene expression patterns that are conveyed by interactions between transcription factors and DNA in the context of chromatin. In development, epigenetic modifiers are thought to stabilize gene expression and ensure that patterns of DNA methylation and histone modification are reinstated in cells as they divide. Global erasure of epigenetic marks occurs naturally at two stages in the mammalian life cycle, but it can also be artificially engineered using a variety of reprogramming strategies. Here we review some of the recent advances in understanding how epigenetic remodeling contributes to conversion of cell fate in vivo and in vitro. We summarize current models of epigenetic erasure and discuss the various enzymes and mechanisms that may operate in cellular reprogramming.
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TL;DR: The transcriptome of human primordial germ cells (PGCs) from the migrating stage to the gonadal stage is analyzed at single-cell and single-base resolutions and paves the way toward deciphering the complex epigenetic reprogramming of the germline with the aim of restoring totipotency in fertilized oocytes.
471 citations
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...The development of mouse primordial germ cells (PGCs) is relatively well understood, including their specification, migration, localization to genital ridges, epigenetic reprogramming, and sex differentiation (Cantone and Fisher, 2013; Lee et al., 2014; Surani et al., 2008)....
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TL;DR: It is shown that a chemical cocktail enables the derivation of stem cells with unique functional and molecular features from mice and humans, designated as extended pluripotent stem (EPS) cells, which are capable of chimerizing both embryonic and extraembryonic tissues.
354 citations
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...This is not surprising considering the complexity of the in vivo niche and developmental processes, e.g., asymmetric epigenetic regulation of paternal and maternal genomes (Cantone and Fisher, 2013)....
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..., asymmetric epigenetic regulation of paternal and maternal genomes (Cantone and Fisher, 2013)....
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TL;DR: This work reports the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers, and describes core regulatory dynamics and shows the lineage-specific behaviour of selected factors.
Abstract: Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics that regulate cell fate changes during mammalian development. Here we report the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers. We describe core regulatory dynamics and show the lineage-specific behaviour of selected factors. In addition to the orchestrated remodelling of the chromatin landscape, we find that the binding of several transcription factors is strongly associated with specific loss of DNA methylation in one germ layer, and in many cases a reciprocal gain in the other layers. Taken together, our work shows context-dependent rewiring of transcription factor binding, downstream signalling effectors, and the epigenome during human embryonic stem cell differentiation.
322 citations
TL;DR: Using breast cancer as a model, it is discussed how an improved understanding of tumor cellular heterogeneity and plasticity may lead to development of more effective therapeutic strategies.
313 citations
Cites background from "Epigenetic programming and reprogra..."
...As a result, the differentiation process is largely unidirectional (Cantone and Fisher, 2013)....
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TL;DR: It is shown that the Arabidopsis long intergenic noncoding RNA (lincRNA) APOLO is transcribed by RNA polymerases II and V in response to auxin, a phytohormone controlling numerous facets of plant development.
304 citations
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...In eukaryotes, gene expression patterns depend on the interactions between transcription factors and the DNA, which can adopt diverse 3D chromatin structural conformations (Cantone and Fisher, 2013)....
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References
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TL;DR: Induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions is demonstrated and iPS cells, designated iPS, exhibit the morphology and growth properties of ES cells and express ES cell marker genes.
23,959 citations
TL;DR: The Encyclopedia of DNA Elements project provides new insights into the organization and regulation of the authors' genes and genome, and is an expansive resource of functional annotations for biomedical research.
Abstract: The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.
13,548 citations
TL;DR: It is shown here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro.
Abstract: DNA cytosine methylation is crucial for retrotransposon silencing and mammalian development. In a computational search for enzymes that could modify 5-methylcytosine (5mC), we identified TET proteins as mammalian homologs of the trypanosome proteins JBP1 and JBP2, which have been proposed to oxidize the 5-methyl group of thymine. We show here that TET1, a fusion partner of the MLL gene in acute myeloid leukemia, is a 2-oxoglutarate (2OG)- and Fe(II)-dependent enzyme that catalyzes conversion of 5mC to 5-hydroxymethylcytosine (hmC) in cultured cells and in vitro. hmC is present in the genome of mouse embryonic stem cells, and hmC levels decrease upon RNA interference–mediated depletion of TET1. Thus, TET proteins have potential roles in epigenetic regulation through modification of 5mC to hmC.
5,155 citations
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
TL;DR: This study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation, and identifies two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins.
Abstract: 5-methylcytosine (5mC) in DNA plays an important role in gene expression, genomic imprinting, and suppression of transposable elements. 5mC can be converted to 5-hydroxymethylcytosine (5hmC) by the Tet (ten eleven translocation) proteins. Here, we show that, in addition to 5hmC, the Tet proteins can generate 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) from 5mC in an enzymatic activity–dependent manner. Furthermore, we reveal the presence of 5fC and 5caC in genomic DNA of mouse embryonic stem cells and mouse organs. The genomic content of 5hmC, 5fC, and 5caC can be increased or reduced through overexpression or depletion of Tet proteins. Thus, we identify two previously unknown cytosine derivatives in genomic DNA as the products of Tet proteins. Our study raises the possibility that DNA demethylation may occur through Tet-catalyzed oxidation followed by decarboxylation.
2,989 citations