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109
Human DNA methylomes at base resolution show widespread epigenomic differences.
- Nature,
, 2009
"... DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryo ..."
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Cited by 401 (6 self)
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DNA cytosine methylation is a central epigenetic modification that has essential roles in cellular processes including genome regulation, development and disease. Here we present the first genome-wide, single-base-resolution maps of methylated cytosines in a mammalian genome, from both human embryonic stem cells and fetal fibroblasts, along with comparative analysis of messenger RNA and small RNA components of the transcriptome, several histone modifications, and sites of DNA-protein interaction for several key regulatory factors. Widespread differences were identified in the composition and patterning of cytosine methylation between the two genomes. Nearly one-quarter of all methylation identified in embryonic stem cells was in a non-CG context, suggesting that embryonic stem cells may use different methylation mechanisms to affect gene regulation. Methylation in non-CG contexts showed enrichment in gene bodies and depletion in protein binding sites and enhancers. Non-CG methylation disappeared upon induced differentiation of the embryonic stem cells, and was restored in induced pluripotent stem cells. We identified hundreds of differentially methylated regions proximal to genes involved in pluripotency and differentiation, and widespread reduced methylation levels in fibroblasts associated with lower transcriptional activity. These reference epigenomes provide a foundation for future studies exploring this key epigenetic modification in human disease and development. Thirty-four years have passed since it was proposed that cytosine DNA methylation in eukaryotes could act as a stably inherited modification affecting gene regulation and cellular differentiation Single-base-resolution maps of DNA methylation for two human cell lines Single-base DNA methylomes of the flowering plant Arabidopsis thaliana were previously achieved using MethylC-Seq 15 or BS-Seq 16 . In this method, genomic DNA is treated with sodium bisulphite (BS) to convert cytosine, but not methylcytosine, to uracil, and subsequent high-throughput sequencing. We performed MethylC-Seq for two human cell lines, H1 human embryonic stem cells 17 and IMR90 fetal lung fibroblasts 18 , generating 1.16 and 1.18 billion reads, respectively, that aligned uniquely to the human reference sequence (NCBI build 36/HG18). The total sequence yield was 87.5 and 91.0 gigabases (Gb), with an average read depth of 14.23 and 14.83 per strand for H1 and IMR90, respectively ( We detected approximately 62 million and 45 million methylcytosines in H1 and IMR90 cells, respectively (1% false discovery rate (FDR), see Supplementary Information and
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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Cited by 269 (2 self)
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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.
Resource Genome-wide High-Resolution Mapping and Functional Analysis of
"... Cytosine methylation is important for transposon silencing and epigenetic regulation of endogenous genes, although the extent to which this DNA modification functions to regulate the genome is still unknown. Here we report the first comprehensive DNA methylation map of an entire genome, at 35 base p ..."
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Cited by 117 (4 self)
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Cytosine methylation is important for transposon silencing and epigenetic regulation of endogenous genes, although the extent to which this DNA modification functions to regulate the genome is still unknown. Here we report the first comprehensive DNA methylation map of an entire genome, at 35 base pair resolution, using the flowering plant Arabidopsis thaliana as a model. We find that pericentromeric heterochromatin, repetitive sequences, and regions producing small interfering RNAs are heavily methylated. Unexpectedly, over onethird of expressed genes contain methylation within transcribed regions, whereas only 5% of genes show methylation within promoter regions. Interestingly, genes methylated in transcribed regions are highly expressed and constitutively active, whereas promoter-methylated genes show a greater degree of tissuespecific expression. Whole-genome tiling-array transcriptional profiling of DNA methyltransferase null mutants identified hundreds of genes and intergenic noncoding RNAs with altered expression levels, many of which may be epigenetically controlled by DNA methylation.
VN: Small RNAs: classification, biogenesis, and function
- Mol Cells
"... Eukaryotes produce various types of small RNAs of 19-28 nt in length. With rapidly increasing numbers of small RNAs listed in recent years, we have come to realize how widespread their functions are and how diverse the biogenesis pathways have evolved. At the same time, we are beginning to grasp the ..."
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Cited by 62 (7 self)
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Eukaryotes produce various types of small RNAs of 19-28 nt in length. With rapidly increasing numbers of small RNAs listed in recent years, we have come to realize how widespread their functions are and how diverse the biogenesis pathways have evolved. At the same time, we are beginning to grasp the common features and rules governing the key steps in small RNA pathways. In this review, I will summarize the current classification, biogenesis, action mechanism and function of these fascinating molecules.
Noncoding transcription by RNA polymerase Pol IVb/Pol V mediates transcriptional silencing of overlapping and adjacent genes
- Cell
, 2008
"... Nuclear transcription is not restricted to genes but occurs throughout the intergenic and noncoding space of eukaryotic genomes. The functional significance of this widespread noncoding transcription is mostly unknown. We show that Arabidopsis RNA polymerase IVb/Pol V, a multisubunit nuclear enzyme ..."
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Cited by 43 (10 self)
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Nuclear transcription is not restricted to genes but occurs throughout the intergenic and noncoding space of eukaryotic genomes. The functional significance of this widespread noncoding transcription is mostly unknown. We show that Arabidopsis RNA polymerase IVb/Pol V, a multisubunit nuclear enzyme required for siRNA-mediated gene silencing of transposons and other repeats, transcribes intergenic and noncoding sequences, thereby facilitating heterochromatin formation and silencing of overlapping and adjacent genes. Pol IVb/Pol V transcription requires the chromatin-remodeling protein DRD1 but is independent of siRNA biogenesis. However, Pol IVb/Pol V transcription and siRNA production are both required to silence transposons, suggesting that Pol IVb/Pol V generates RNAs or chromatin structures that serve as scaffolds for siRNA-mediated heterochromatinforming complexes. Pol IVb/Pol V function provides a solution to a paradox of epigenetic control: the need for transcription in order to transcriptionally silence the same region.
Finding the fifth base: Genome-wide sequencing of cytosine methylation. Genome Res
, 2009
"... methylation ..."
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From genome to epigenome
- Human Molecular Genetics, 14(Review Issue 1):R3–R10, 15April 2005. http://hmg.oxfordjournals.org/cgi/content/abstract/14/suppl 1/R3
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TranspoGene and microTranspoGene: transposed elements influence on the transcriptome of seven vertebrates and invertebrates
- Nucleic Acids Res
, 2007
"... elements influence on the transcriptome of seven vertebrates and invertebrates ..."
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Cited by 21 (8 self)
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elements influence on the transcriptome of seven vertebrates and invertebrates
Empirical comparison of ab initio repeat finding programs
- Nucleic Acids Research
"... doi:10.1093/nar/gkn064 ..."
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