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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 28 January 2014, Vol.111(4), pp.1361-6
    Description: Dioxygenases of the Ten-Eleven Translocation (TET) family are 5-methylcytosine oxidases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products in DNA. We show that Tet1 and Tet2 have distinct roles in regulating 5hmC in mouse embryonic stem cells (mESC). Tet1 depletion diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is predominantly associated with decreased 5hmC in gene bodies. Enrichment of 5hmC is observed at the boundaries of exons that are highly expressed, and Tet2 depletion results in substantial loss of 5hmC at these boundaries. In contrast, at promoter/TSS regions, Tet2 depletion results in increased 5hmC, potentially because of the redundant activity of Tet1. Together, the data point to a complex interplay between Tet1 and Tet2 in mESC, and to distinct roles for these two proteins in regulating promoter, exon, and polyadenylation site usage in cells.
    Keywords: DNA Demethylation ; DNA Hydroxymethylation ; DNA Methylation ; Epigenetics ; DNA-Binding Proteins -- Physiology ; Embryonic Stem Cells -- Metabolism ; Proto-Oncogene Proteins -- Physiology
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences, 12/20/2016, Vol.113(51), pp.E8267-E8276
    Description: TET-family dioxygenases catalyze conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and oxidized methylcytosines in DNA. Here, we show that mouse embryonic stem cells (mESCs), either lacking Tet3 alone or with triple deficiency of Tet1/2/3, displayed impaired adoption of neural cell fate and concomitantly skewed toward cardiac mesodermal fate. Conversely, ectopic expression of Tet3 enhanced neural differentiation and limited cardiac mesoderm specification. Genome-wide analyses showed that Tet3 mediates cell-fate decisions by inhibiting Wnt signaling, partly through promoter demethylation and transcriptional activation of the Wnt inhibitor secreted frizzled-related protein 4 (Sfrp4). Tet1/2/3-deficient embryos (embryonic day 8.0-8.5) showed hyperactivated Wnt signaling, as well as aberrant differentiation of bipotent neuromesodermal progenitors (NMPs) into mesoderm at the expense of neuroectoderm. Our data demonstrate a key role for TET proteins in modulating Wnt signaling and establishing the proper balance between neural and mesodermal cell fate determination in mouse embryos and ESCs.
    Keywords: Sciences (General);
    ISSN: 0027-8424
    E-ISSN: 1091-6490
    Source: CrossRef
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 04 August 2015, Vol.112(31), pp.E4236-45
    Description: Dioxygenases of the TET (Ten-Eleven Translocation) family produce oxidized methylcytosines, intermediates in DNA demethylation, as well as new epigenetic marks. Here we show data suggesting that TET proteins maintain the consistency of gene transcription. Embryos lacking Tet1 and Tet3 (Tet1/3 DKO) displayed a strong loss of 5-hydroxymethylcytosine (5hmC) and a concurrent increase in 5-methylcytosine (5mC) at the eight-cell stage. Single cells from eight-cell embryos and individual embryonic day 3.5 blastocysts showed unexpectedly variable gene expression compared with controls, and this variability correlated in blastocysts with variably increased 5mC/5hmC in gene bodies and repetitive elements. Despite the variability, genes encoding regulators of cholesterol biosynthesis were reproducibly down-regulated in Tet1/3 DKO blastocysts, resulting in a characteristic phenotype of holoprosencephaly in the few embryos that survived to later stages. Thus, TET enzymes and DNA cytosine modifications could directly or indirectly modulate transcriptional noise, resulting in the selective susceptibility of certain intracellular pathways to regulation by TET proteins.
    Keywords: 5-Hydroxymethylcytosine ; 5hmc ; DNA Methylation ; Tet Methylcytosine Oxidases ; Cholesterol Biosynthesis ; Gene Deletion ; Gene Expression Regulation, Developmental ; 5-Methylcytosine -- Metabolism ; DNA-Binding Proteins -- Metabolism ; Embryonic Development -- Genetics ; Proto-Oncogene Proteins -- Metabolism ; Transcriptome -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    In: Nature, 2013, Vol.497(7447), p.122
    Description: TET (ten-eleven-translocation) proteins are Fe(ii)- and α-ketoglutarate-dependent dioxygenases that modify the methylation status of DNA by successively oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxycytosine, potential intermediates in the active erasure of DNA-methylation marks. Here we show that IDAX (also known as CXXC4), a reported inhibitor of Wnt signalling that has been implicated in malignant renal cell carcinoma and colonic villous adenoma, regulates TET2 protein expression. IDAX was originally encoded within an ancestral TET2 gene that underwent a chromosomal gene inversion during evolution, thus separating the TET2 CXXC domain from the catalytic domain. The IDAX CXXC domain binds DNA sequences containing unmethylated CpG dinucleotides, localizes to promoters and CpG islands in genomic DNA and interacts directly with the catalytic domain of TET2. Unexpectedly, IDAX expression results in caspase activation and TET2 protein downregulation, in a manner that depends on DNA binding through the IDAX CXXC domain, suggesting that IDAX recruits TET2 to DNA before degradation. IDAX depletion prevents TET2 downregulation in differentiating mouse embryonic stem cells, and short hairpin RNA against IDAX increases TET2 protein expression in the human monocytic cell line U937. Notably, we find that the expression and activity of TET3 is also regulated through its CXXC domain. Taken together, these results establish the separate and linked CXXC domains of TET2 and TET3, respectively, as previously unknown regulators of caspase activation and TET enzymatic activity.
    Keywords: 5-Methylcytosine -- Metabolism ; DNA-Binding Proteins -- Chemistry ; Proto-Oncogene Proteins -- Metabolism ; Transcription Factors -- Chemistry;
    ISSN: 0028-0836
    E-ISSN: 14764687
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  • 5
    In: Nature, 2018
    Description: Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.
    Keywords: DNA Methylation ; Tumors ; Standardization ; Data Processing ; Classification ; Methylation ; Brain Cancer ; Bioinformatics ; Cancer ; Generalized Linear Models ; DNA Methylation ; Diagnosis ; Tumors ; Genomes ; Classification ; Central Nervous System ; Central Nervous System ; Diagnosis ; Cancer ; Learning Algorithms ; Diagnostic Software ; Data Processing ; Tumors ; Central Nervous System ; Gene Expression ; Standardization ; Classification ; Cancer ; Classifiers ; Classification ; Clinical Trials ; Deoxyribonucleic Acid–DNA ; Probability ; Diagnostic Systems ; Nervous System ; Methylation ; Data Processing ; Tumors ; Data Processing ; Deoxyribonucleic Acid–DNA ; Deoxyribonucleic Acid–DNA ; World Health Organization;
    ISSN: 0028-0836
    E-ISSN: 1476-4687
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  • 6
    Language: English
    In: PLoS ONE, 2010, Vol.5(5), p.e10709
    Description: It is essential to understand the network of transcription factors controlling self-renewal of human embryonic stem cells (ESCs) and human embryonal carcinoma cells (ECs) if we are to exploit these cells in regenerative medicine regimes. Correlating gene expression levels after RNAi-based ablation of OCT4 function with its downstream targets enables a better prediction of motif-specific driven expression modules pertinent for self-renewal and differentiation of embryonic stem cells and induced pluripotent stem cells. ; We initially identified putative direct downstream targets of OCT4 by employing CHIP-on-chip analysis. A comparison of three peak analysis programs revealed a refined list of OCT4 targets in the human EC cell line NCCIT, this list was then compared to previously published OCT4 CHIP-on-chip datasets derived from both ES and EC cells. We have verified an enriched POU-motif, discovered by a approach, thus enabling us to define six distinct modules of OCT4 binding and regulation of its target genes. ; A selection of these targets has been validated, like NANOG, which harbours the evolutionarily conserved OCT4-SOX2 binding motif within its proximal promoter. Other validated targets, which do not harbour the classical HMG motif are USP44 and GADD45G, a key regulator of the cell cycle. Over-expression of GADD45G in NCCIT cells resulted in an enrichment and up-regulation of genes associated with the cell cycle (, , and ) and developmental processes (, , , , , , and ). A comparison of positively regulated OCT4 targets common to EC and ES cells identified genes such as , , , , , thus further confirming their universal role in maintaining self-renewal in both cell types. Finally we have created a user-friendly database (), integrating all OCT4 and stem cell related datasets in both human and mouse ES and EC cells. ; In the current era of systems biology driven research, we envisage that our integrated embryonic stem cell database will prove beneficial to the booming field of ES, iPS and cancer research.
    Keywords: Research Article ; Biochemistry -- Transcription And Translation ; Computational Biology -- Systems Biology ; Computational Biology -- Transcriptional Regulation ; Developmental Biology -- Cell Differentiation ; Developmental Biology -- Embryology ; Developmental Biology -- Stem Cells ; Genetics And Genomics -- Bioinformatics ; Genetics And Genomics -- Comparative Genomics ; Genetics And Genomics -- Functional Genomics ; Genetics And Genomics -- Gene Expression
    E-ISSN: 1932-6203
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  • 7
    In: PLoS ONE, 2013, Vol.8(1)
    Description: Genome-wide association studies (GWASs) identify single nucleotide polymorphisms (SNPs) that are enriched in individuals suffering from a given disease. Most disease-associated SNPs fall into non-coding regions, so that it is not straightforward to infer phenotype or function; moreover, many SNPs are in tight genetic linkage, so that a SNP identified as associated with a particular disease may not itself be causal, but rather signify the presence of a linked SNP that is functionally relevant to disease pathogenesis. Here, we present an analysis method that takes advantage of the recent rapid accumulation of epigenomics data to address these problems for some SNPs. Using asthma as a prototypic example; we show that non-coding disease-associated SNPs are enriched in genomic regions that function as regulators of transcription, such as enhancers and promoters. Identifying enhancers based on the presence of the histone modification marks such as H3K4me1 in different cell types, we show that the location of enhancers is highly cell-type specific. We use these findings to predict which SNPs are likely to be directly contributing to disease based on their presence in regulatory regions, and in which cell types their effect is expected to be detectable. Moreover, we can also predict which cell types contribute to a disease based on overlap of the disease-associated SNPs with the locations of enhancers present in a given cell type. Finally, we suggest that it will be possible to re-analyze GWAS studies with much higher power by limiting the SNPs considered to those in coding or regulatory regions of cell types relevant to a given disease.
    Keywords: Research Article ; Biology
    E-ISSN: 1932-6203
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  • 8
    Language: English
    In: Cancer Research, 07/15/2016, Vol.76(14 Supplement), pp.SY15-02-SY15-02
    Description: Malignant pediatric brain tumors, including ependymoma, medulloblastoma and atypical teratoidrhabdoid tumors, frequently demonstrate a very quiet genome with very few nonsynonyomous single nucleotide variants or indels and a stable copy number profile. The recent advance of integrative genomics approaches from primary tumor tissue including whole-genome sequencing, RNA sequencing, whole-genome bisulfite sequencing, and ChIP sequencing for core histone marks and important transcription factors and chromatin configuration have enabled the discovery of new tumor-driving pathways and potentially druggable alterations in these cancers with quiet genomes. This knowledge after functional validation in vitro and in vivo provides critical insight in the search for the cell of origin in these tumors, the understanding of underlying pathomechanisms, and the identification of new treatment options.
    Keywords: Brain Mapping ; Histones ; Chromatin ; Pediatrics ; Landscape ; Bisulfite ; Nucleotides ; Cancer ; Copy Number ; Brain Tumors ; Enhancers ; RNA ; Transcription Factors ; Medulloblastoma ; Genomics ; Gene Mapping ; Development & Cell Cycle ; Miscellaneous Oncogenes & Growth Factors;
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 9
    Book
    Book
    Bentham Science Publishers Ltd.
    Language: English
    Keywords: Functional Genomics Mouse Embryonic Stem Cells Microarray Analysis Fungenes Database Gene Expression Profiling Bioinformatics Gene Clustering Time Waves Expression Waves Pathway Animations Multi-Experiment Matrix G:Profiler.
    Source: Bentham Science Publishers
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  • 10
    Book chapter
    Book chapter
    Bentham Science Publishers Ltd.
    Language: English
    In: Computational Biology of Embryonic Stem Cells, pp.88-108
    Description: Methylation of cytosines is a reversible and dynamic epigenetic DNA modification emerging during differentiation of human embryonic stem cells (hESCs) and throughout mammalian development. Crucial advancements in sequencing technologies have enabled the analysis of DNA methylation on a full genome level. Several studies recently examined the methylomes of hESCs, and investigated genetic and epigenetic dependencies during early differentiation. Methylated DNA immunoprecipitation (MeDIP) followed by high-throughput sequencing (MeDIP-seq) has become a cost-efficient experimental approach for genome wide epigenetic studies. However, it has been shown that MeDIP-seq data has to be corrected for a DNA sequence composition dependent bias in order to produce valid methylation profiles. Therefore, the development and implementation of time-efficient computational methods able to process large amounts of sequencing data with respect to its inherent complexity, is crucial for reducing the imbalance of sequencing data generation and analysis. This chapter introduces to different experimental techniques available for full genome methylation analysis. Subsequently, time efficient algorithms for processing MeDIP-seq data as well as different concepts for normalization are presented. Finally, recent findings of genetic and epigenetic dependencies in hESCs are summarized.
    Keywords: Dna Methylation ; Cpg Islands ; Transcription Factor Binding Sites ; Immunoprecipitation ; Epigenetics ; Differentiation ; Medip ; Medip-Seq ; Next ; Generation Sequencing ; Linear Model ; Medips ; Regulation ; Transcriptional ; Pluripotency ; Normalization.
    Source: Bentham Science Publishers
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