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- Birney, Ewan, et al.
(författare)
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Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project
- 2007
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 447:7146, s. 799-816
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Tidskriftsartikel (refereegranskat)abstract
- We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.
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| 2. |
- Roy, Sushmita, et al.
(författare)
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Identification of functional elements and regulatory circuits by Drosophila modENCODE.
- 2010
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Ingår i: Science (New York, N.Y.). - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 330:6012, s. 1787-1797
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Tidskriftsartikel (refereegranskat)abstract
- To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
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| 3. |
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| 4. |
- Milani, Lili, 1981-
(författare)
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Gene Expression in Cancer Cells : Detection of Splice Variants, Allele-specific Expression and DNA Methylation
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human genome sequencing project has provided a wealth of information on sequence variation between individuals. The surprisingly low number of genes in the human genome is compensated for by a complex regulation of gene expression. New methods are now being developed for the discovery and analysis of the regulatory regions of the genome to elucidate factors that affect both normal and disease-associated human genetic variation. In parallel with identification of DNA sequence variation, efforts are being made to unravel the next layer of information - epigenetic modifications of the genome. The studies in this thesis describe the application of methods for genotyping single nucleotide polymorphisms (SNPs) in DNA for the analysis of gene transcripts in cancer cells. We performed quantitative analysis of splice variants and screened for allele-specific gene expression (ASE) in cancer cells using the tag-microarray based minisequencing system. This analysis revealed transcript isoforms that were differentially spliced in leukemia cell lines and normal endothelial cell lines. We detected wide-spread allele-specific gene expression in cancer cells that were sensitive or resistant to anti-cancer drugs. In regulatory regions of the genes with ASE we identified putative regulatory SNPs. Using technology developed for large-scale SNP genotyping, we screened for ASE in an internationally unique collection of childhood acute lymphoblastic leukemia (ALL) samples. Analysis of DNA methylation in promoter regions of genes displaying ASE revealed genes, whose expression is regulated by allele-specific DNA methylation. For a subset of these genes we found a correlation between DNA methylation levels and probability of disease-free survival in ALL patients with different chromosomal aberrations. The methylation patterns that we identified constitute excellent candidate markers for subtyping of ALL patients and for stratification of ALL patients based on their probability of disease-free survival and response to drug treatment. The results of this study have increased our understanding of epigenetic changes in ALL cells and will hopefully help to design better treatment plans for the patients to avoid over-treatment and unnecessary side effects.
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