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269
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
Mapping and analysis of chromatin state dynamics in nine human cell types,”
- Nature,
, 2011
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FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132: 958–970
, 2008
"... Complex organisms require tissue-specific transcriptional programs, yet little is known about how these are established. The transcription factor FoxA1 is thought to contribute to gene regulation through its ability to act as a pioneer factor binding to nucleosomal DNA. Through genome-wide positiona ..."
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Cited by 117 (13 self)
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Complex organisms require tissue-specific transcriptional programs, yet little is known about how these are established. The transcription factor FoxA1 is thought to contribute to gene regulation through its ability to act as a pioneer factor binding to nucleosomal DNA. Through genome-wide positional analyses, we demonstrate that FoxA1 cell type-specific functions rely primarily on differential recruitment to chromatin predominantly at distant enhancers rather than proximal promoters. This differential recruitment leads to cell type-specific changes in chromatin structure and functional collaboration with lineage-specific transcription factors. Despite the ability of FoxA1 to bind nucleosomes, its differential binding to chromatin sites is dependent on the distribution of histone H3 lysine 4 dimethylation. Together, our results suggest that methylation of histone H3 lysine 4 is part of the epigenetic signature that defines lineage-specific FoxA1 recruitment sites in chromatin. FoxA1 translates this epigenetic signature into changes in chromatin structure thereby establishing lineage-specific transcriptional enhancers and programs.
Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors,”
- Cell,
, 2010
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Germline competent embryonic stem cells derived from rat blastocysts. Cell 135: 1299
, 2008
"... Rats have important advantages over mice as an experimental system for physiological and pharmacological investigations. The lack of rat embryonic stem (ES) cells has restricted the availability of transgenic technologies to create genetic models in this species. Here, we show that rat ES cells can ..."
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Cited by 61 (2 self)
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Rats have important advantages over mice as an experimental system for physiological and pharmacological investigations. The lack of rat embryonic stem (ES) cells has restricted the availability of transgenic technologies to create genetic models in this species. Here, we show that rat ES cells can be efficiently derived, propagated, and genetically manipulated in the presence of small molecules that specifically inhibit GSK3, MEK, and FGF receptor tyrosine kinases. These rat ES cells express pluripotency markers and retain the capacity to differentiate into derivatives of all three germ layers. Most importantly, they can produce high rates of chimerism when reintroduced into early stage embryos and can transmit through the germline. Establishment of authentic rat ES cells will make possible sophisticated genetic manipulation to create models for the study of human diseases.
Comprehensive analysis of the chromatin landscape in Drosophila melanogaster
"... Chromatin, the composite of DNA and its associated proteins, occurs in various conformations in living cells and is essential for cell differentiation, gene regulation and other key cellular processes. We present a genomewide map of the chromatin landscape for Drosophila melanogaster, based on the d ..."
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Cited by 49 (5 self)
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Chromatin, the composite of DNA and its associated proteins, occurs in various conformations in living cells and is essential for cell differentiation, gene regulation and other key cellular processes. We present a genomewide map of the chromatin landscape for Drosophila melanogaster, based on the distributions of 18 histone modifications and 9 combinatorial patterns identified by computational analysis. Integrative analysis with other
seqMINER: an integrated ChIP-seq data interpretation platform
- Nucleic Acids Res
, 2011
"... In a single experiment, chromatin immunopre-cipitation combined with high throughput sequencing (ChIP-seq) provides genome-wide infor-mation about a given covalent histone modification or transcription factor occupancy. However, time ef-ficient bioinformatics resources for extracting bio-logical mea ..."
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Cited by 31 (4 self)
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In a single experiment, chromatin immunopre-cipitation combined with high throughput sequencing (ChIP-seq) provides genome-wide infor-mation about a given covalent histone modification or transcription factor occupancy. However, time ef-ficient bioinformatics resources for extracting bio-logical meaning out of these gigabyte-scale datasets are often a limiting factor for data interpret-ation by biologists. We created an integrated portable ChIP-seq data interpretation platform called seqMINER, with optimized performances for efficient handling of multiple genome-wide datasets. seqMINER allows comparison and integration of multiple ChIP-seq datasets and extraction of quali-tative as well as quantitative information. seqMINER can handle the biological complexity of most experi-mental situations and proposes methods to the user for data classification according to the analysed features. In addition, through multiple graphical rep-resentations, seqMINER allows visualization and modelling of general as well as specific patterns in a given dataset. To demonstrate the efficiency of seqMINER, we have carried out a comprehensive analysis of genome-wide chromatin modification data in mouse embryonic stem cells to understand the global epigenetic landscape and its change through cellular differentiation.
A profile of histone lysine methylation across transcribed mammalian chromatin
- Mol. Cell Biol
, 2006
"... This article cites 79 articles, 31 of which can be accessed free ..."
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Cited by 26 (1 self)
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This article cites 79 articles, 31 of which can be accessed free
Resource Combinatorial Patterning of Chromatin Regulators Uncovered by Genome-wide Location Analysis in Human Cells
"... Hundreds of chromatin regulators (CRs) control chromatin structure and function by catalyzing and binding histone modifications, yet the rules governing these key processes remain obscure. Here, we present a systematic approach to infer CR function. We developed ChIP-string, a meso-scale assay that ..."
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Cited by 20 (3 self)
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Hundreds of chromatin regulators (CRs) control chromatin structure and function by catalyzing and binding histone modifications, yet the rules governing these key processes remain obscure. Here, we present a systematic approach to infer CR function. We developed ChIP-string, a meso-scale assay that combines chromatin immunoprecipitation with a signature readout of 487 representative loci. We applied ChIP-string to screen 145 antibodies, thereby identifying effective reagents, which we used to map the genome-wide binding of 29 CRs in two cell types. We found that specific combinations of CRs colocalize in characteristic patterns at distinct chromatin environments, at genes of coherent functions, and at distal regulatory elements. When comparing between cell types, CRs redistribute to different loci but maintain their modular and combinatorial associations. Our work provides a multiplex method that substantially enhances the ability to monitor CR binding, presents a large resource of CR maps, and reveals common principles for combinatorial CR function.
