1,721,006 research outputs found
Association of global CpG methylation status with gene expression phenotypes in normal and cancer cells
No full textAssociation of global CpG methylation status with gene expression phenotypes in normal and cancer cells
Anna DE GRASSI
Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, via Orabona 4, 70125, Bari, Italy
Cytosine methylation at CpG dinucleotides is a major mechanism of epigenetic regulation of gene expression, whereas methylation of promoters and demethylation of gene bodies are typically associated with transcriptional repression and vice versa (1). Poor is instead known about the forces that generate variable degrees of global CpG methylation in the genomes of different cells and how the gene expression phenotypes are consequently altered. The ENCODE project has recently furnished and invaluable data platform for this investigation, by systematically performing high-throughput experiments in several human cell lines (2). Forty-five normal and cancer cell lines were collected from the ENCODE platform for which both reduced representation bisulfite sequencing (RRBS) data and exon array data are publicly available. A subset of ~130,000 CpG sites scattered throughout the genome were selected for the high reproducibility among RRBS replicates and were used to estimate the global CpG methylation status of each cell line. Using this estimation, cancer cell lines were distinguishable from primary cell lines with 100% sensitivity and specificity. The global CpG methylation degree was higher in cancer cells than in normal cells in all the genome compartments (exons, introns, promoter and intergenic regions), suggesting that at least one component of the CpG methylation profile of cancer cells is due to a basal and homogeneous hypermethylation along the genome. By comparing the CpG methylation status of cell lines and the expression level of ~20,000 genes in the same cell set, several genes were detected whose expression profile significantly correlates with the global CpG methylation degree. The top positively correlated genes include DNA methyltransferases and genes encoding proteins involved in nucleosome organization and assembly, as well as in histone exchange. Beside furnishing a list of candidate genes whose expression profile associates with the hypermethylation of cancer cells, these results suggest that an increased global CpG methylation status might be determined by the over-expression of DNA methyltransferases, and not by the transcriptional repression of DNA demethylator genes, and by an extensive remodeling of chromatin.
References:
1. Ball MP et al. Nat Biotechnol. 27, 361-368 (2009). doi: 10.1038/nbt.1533.
2. Encode Project Consortium. Nature 489, 57-74 (2012). doi: 10.1038/nature11247
Method for Detecting or Diagnosing Genomic Instability
No full textA method is provided for detecting or diagnosing genomic instability in an individual by determining the difference in mutation frequency between a non-conserved genomic region and an ultra-conserved genomic region (UCR), where a statistically significant increase in mutation frequency in the non-conserved region as compared to the UCR establishes a likelihood of genomic instability in the individual
Tandem repeats modify the structure of human genes hosted in segmental duplications
Full text linkBACKGROUND:Recently duplicated genes are often subject to genomic rearrangements that can lead to the development of novel gene structures. Here we specifically investigated the effect of variations in internal tandem repeats (ITRs) on the gene structure of human paralogs located in segmental duplications.RESULTS:We found that around 7% of the primate-specific genes located within duplicated regions of the genome contain variable tandem repeats. These genes are members of large groups of recently duplicated paralogs that are often polymorphic in the human population. Half of the identified ITRs occur within coding exons and may be either kept or spliced out from the mature transcript. When ITRs reside within exons, they encode variable amino acid repeats. When located at exon-intron boundaries, ITRs can generate alternative splicing patterns through the formation of novel introns.CONCLUSIONS:Our study shows that variation in the number of ITRs impacts on recently duplicated genes by modifying their coding sequence, splicing pattern, and tissue expression. The resulting effect is the production of a variety of primate-specific proteins, which mostly differ in number and sequence of amino acid repeats
Evolution of ATP synthase subunit c and cytochrome c gene families in selected Metazoan classes
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Lattices for ab initio protein structure prediction
No full textIn the study of the protein folding problem with ab initio methods, the protein backbone can be built on some periodic lattices. Any vertex of these lattices can be occupied by a "ball," which can represent the mass center of an amino acid in a simplified coarse-grained model of the protein. The backbone, at a coarse-grained level, can be constituted of a No Reverse Self Avoiding Walk, which cannot intersect itself and cannot go back on itself. There is still much debate between those who use lattices to simplify the study of the protein folding problem and those preferring to work by using an off-lattice approach. Lattices can help to identify the protein tertiary structure in a computational less-expensive way, than off-lattice approaches that have to consider a potentially infinite number of possible structures. However, the use of a lattice, constituted of insufficiently accurate direction vectors, constrains the predictive ability of the model. The aim of this study is to perform a systematic screening of 7 known classic and 11 newly proposed lattices in terms of predictive power. The crystal structures of 42 different proteins (14 mainly alpha helical, 14 mainly beta sheet and 14 mixed structure proteins) were compared to the most accurate simulated models for each lattice. This strategy defines a scale of fitness for all the analyzed lattices and demonstrates that an increase in the coordination number and in the degrees of freedom is necessary but not sufficient to reach the best result. Instead, the introduction of a good set of direction vectors, as developed and tested in this study, strongly increases the lattice performance
Metazoan OXPHOS gene families: Evolutionary forces at the level of mitochondrial and nuclear genomes
No full textAbstractMitochondrial and nuclear DNAs contribute to encode the whole mitochondrial protein complement. The two genomes possess highly divergent features and properties, but the forces influencing their evolution, even if different, require strong coordination. The gene content of mitochondrial genome in all Metazoa is in a frozen state with only few exceptions and thus mitochondrial genome plasticity especially concerns some molecular features, i.e. base composition, codon usage, evolutionary rates. In contrast the high plasticity of nuclear genomes is particularly evident at the macroscopic level, since its redundancy represents the main feature able to introduce genetic material for evolutionary innovations. In this context, genes involved in oxidative phosphorylation (OXPHOS) represent a classical example of the different evolutionary behaviour of mitochondrial and nuclear genomes. The simple DNA sequence of Cytochrome c oxidase I (encoded by the mitochondrial genome) seems to be able to distinguish intra- and inter-species relations between organisms (DNA Barcode). Some OXPHOS subunits (cytochrome c, subunit c of ATP synthase and MLRQ) are encoded by several nuclear duplicated genes which still represent the trace of an ancient segmental/genome duplication event at the origin of vertebrates
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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