1. |
- 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. |
- Ameur, Adam, et al.
(författare)
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The LCB Data Warehouse
- 2006
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 22:8, s. 1024-1026
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Tidskriftsartikel (refereegranskat)abstract
- The Linnaeus Centre for Bioinformatics Data Warehouse (LCB-DWH) is a web-based infrastructure for reliable and secure microarray gene expression data management and analysis that provides an online service for the scientific community. The LCB-DWH is an effort towards a complete system for storage (using the BASE system), analysis and publication of microarray data. Important features of the system include: access to established methods within R/Bioconductor for data analysis, built-in connection to the Gene Ontology database and a scripting facility for automatic recording and re-play of all the steps of the analysis. The service is up and running on a high performance server. At present there are more than 150 registered users.
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3. |
- Andersson, Robin, et al.
(författare)
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Nucleosomes are well positioned in exons and carry characteristic histone modifications
- 2009
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 19:10, s. 1732-1741
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Tidskriftsartikel (refereegranskat)abstract
- The genomes of higher organisms are packaged in nucleosomes with functional histone modifications. Until now, genome-wide nucleosome and histone modification studies have focused on transcription start sites (TSSs) where nucleosomes in RNA polymerase II (RNAPII) occupied genes are well positioned and have histone modifications that are characteristic of expression status. Using public data, we here show that there is a higher nucleosome-positioning signal in internal human exons and that this positioning is independent of expression. We observed a similarly strong nucleosome-positioning signal in internal exons of C. elegans. Among the 38 histone modifications analyzed in man, H3K36me3, H3K79me1, H2BK5me1, H3K27me1, H3K27me2 and H3K27me3 had evidently higher signal in internal exons than in the following introns and were clearly related to exon expression. These observations are suggestive of roles in splicing. Thus, exons are not only characterized by their coding capacity but also by their nucleosome organization, which seems evolutionary conserved since it is present in both primates and nematodes.
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4. |
- Draminski, Michal, et al.
(författare)
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Monte Carlo feature selection for supervised classification
- 2008
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Ingår i: Bioinformatics. - : Oxford University Press (OUP). - 1367-4803 .- 1367-4811. ; 24:1, s. 110-117
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Tidskriftsartikel (refereegranskat)abstract
- MOTIVATION: Pre-selection of informative features for supervised classification is a crucial, albeit delicate, task. It is desirable that feature selection provides the features that contribute most to the classification task per se and which should therefore be used by any classifier later used to produce classification rules. In this article, a conceptually simple but computer-intensive approach to this task is proposed. The reliability of the approach rests on multiple construction of a tree classifier for many training sets randomly chosen from the original sample set, where samples in each training set consist of only a fraction of all of the observed features. RESULTS: The resulting ranking of features may then be used to advantage for classification via a classifier of any type. The approach was validated using Golub et al. leukemia data and the Alizadeh et al. lymphoma data. Not surprisingly, we obtained a significantly different list of genes. Biological interpretation of the genes selected by our method showed that several of them are involved in precursors to different types of leukemia and lymphoma rather than being genes that are common to several forms of cancers, which is the case for the other methods.
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5. |
- Motallebipour, Mehdi, et al.
(författare)
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Novel genes in cell cycle control and lipid metabolism with dynamically regulated binding sites for sterol regulatory element-binding protein 1 and RNA polymerase II in HepG2 cells detected by chromatin immunoprecipitation with microarray detection
- 2009
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Ingår i: The FEBS Journal. - : Wiley. - 1742-464X .- 1742-4658. ; 276:7, s. 1878-1890
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Tidskriftsartikel (refereegranskat)abstract
- Sterol regulatory element-binding proteins 1 and 2 (SREBP-1 and SREBP-2) are important regulators of genes involved in cholesterol and fatty acid metabolism, but have also been implicated in the regulation of the cell cycle and have been associated with the pathogenesis of type 2 diabetes, atherosclerosis and obesity, among others. In this study, we aimed to characterize the binding sites of SREBP-1 and RNA polymerase II through chromatin immunoprecipitation and microarray analysis in 1% of the human genome, as defined by the Encyclopaedia of DNA Elements consortium, in a hepatocellular carcinoma cell line (HepG2). Our data identified novel binding sites for SREBP-1 in genes directly or indirectly involved in cholesterol metabolism, e.g. apolipoprotein C-III (APOC3). The most interesting biological findings were the binding sites for SREBP-1 in genes for host cell factor C1 (HCFC1), involved in cell cycle regulation, and for filamin A (FLNA). For RNA polymerase II, we found binding sites at classical promoters, but also in intergenic and intragenic regions. Furthermore, we found evidence of sterol-regulated binding of SREBP-1 and RNA polymerase II to HCFC1 and FLNA. From the results of this work, we infer that SREBP-1 may be involved in processes other than lipid metabolism.
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6. |
- Pandey, Radha Raman, et al.
(författare)
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Kcnq1ot1 antisense noncoding RNA mediates lineage-specific transcriptional silencing through chromatin-level regulation
- 2008
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Ingår i: Molecular Cell. - : Elsevier BV. - 1097-2765 .- 1097-4164. ; 32:2, s. 232-46
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Tidskriftsartikel (refereegranskat)abstract
- Recent investigations have implicated long antisense noncoding RNAs in the epigenetic regulation of chromosomal domains. Here we show that Kcnq1ot1 is an RNA polymerase II-encoded, 91 kb-long, moderately stable nuclear transcript and that its stability is important for bidirectional silencing of genes in the Kcnq1 domain. Kcnq1ot1 interacts with chromatin and with the H3K9- and H3K27-specific histone methyltransferases G9a and the PRC2 complex in a lineage-specific manner. This interaction correlates with the presence of extended regions of chromatin enriched with H3K9me3 and H3K27me3 in the Kcnq1 domain in placenta, whereas fetal liver lacks both chromatin interactions and heterochromatin structures. In addition, the Kcnq1 domain is more often found in contact with the nucleolar compartment in placenta than in liver. Taken together, our data describe a mechanism whereby Kcnq1ot1 establishes lineage-specific transcriptional silencing patterns through recruitment of chromatin remodeling complexes and maintenance of these patterns through subsequent cell divisions occurs via targeting the associated regions to the perinucleolar compartment.
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7. |
- Rada-Iglesias, Alvaro, et al.
(författare)
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Binding sites for metabolic disease related transcription factors inferred at base pair resolution by chromatin immunoprecipitation and genomic microarrays
- 2005
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 14:22, s. 3435-3447
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Tidskriftsartikel (refereegranskat)abstract
- We present a detailed in vivo characterization of hepatocyte transcriptional regulation in HepG2 cells, using chromatin immunoprecipitation and detection on PCR fragment-based genomic tiling path arrays covering the encyclopedia of DNA element (ENCODE) regions. Our data suggest that HNF-4α and HNF-3β, which were commonly bound to distal regulatory elements, may cooperate in the regulation of a large fraction of the liver transcriptome and that both HNF-4α and USF1 may promote H3 acetylation to many of their targets. Importantly, bioinformatic analysis of the sequences bound by each transcription factor (TF) shows an over-representation of motifs highly similar to the in vitro established consensus sequences. On the basis of these data, we have inferred tentative binding sites at base pair resolution. Some of these sites have been previously found by in vitro analysis and some were verified in vitro in this study. Our data suggests that a similar approach could be used for the in vivo characterization of all predicted/uncharacterized TF and that the analysis could be scaled to the whole genome.
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8. |
- Rada-Iglesias, Alvaro, et al.
(författare)
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Butyrate mediates decrease of histone acetylation centered on transcription start sites and down-regulation of associated genes
- 2007
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 17:6, s. 708-719
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Tidskriftsartikel (refereegranskat)abstract
- Butyrate is a histone deacetylase inhibitor (HDACi) with anti-neoplastic properties, which theoretically reactivates epigenetically silenced genes by increasing global histone acetylation. However, recent studies indicate that a similar number or even more genes are down-regulated than up-regulated by this drug. We treated hepatocarcinoma HepG2 cells with butyrate and characterized the levels of acetylation at DNA-bound histones H3 and H4 by ChIP-chip along the ENCODE regions. In contrast to the global increases of histone acetylation, many genomic regions close to transcription start sites were deacetylated after butyrate exposure. In order to validate these findings, we found that both butyrate and trichostatin A treatment resulted in histone deacetylation at selected regions, while nucleosome loss or changes in histone H3 lysine 4 trimethylation (H3K4me3) did not occur in such locations. Furthermore, similar histone deacetylation events were observed when colon adenocarcinoma HT-29 cells were treated with butyrate. In addition, genes with deacetylated promoters were down-regulated by butyrate, and this was mediated at the transcriptional level by affecting RNA polymerase II (POLR2A) initiation/elongation. Finally, the global increase in acetylated histones was preferentially localized to the nuclear periphery, indicating that it might not be associated to euchromatin. Our results are significant for the evaluation of HDACi as anti-tumourogenic drugs, suggesting that previous models of action might need to be revised, and provides an explanation for the frequently observed repression of many genes during HDACi treatment.
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9. |
- Rada-Iglesias, A., et al.
(författare)
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Histone H3 lysine 27 trimethylation in adult differentiated colon associated to cancer DNA hypermethylation
- 2009
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Ingår i: Epigenetics. - 1559-2294. ; 4:2, s. 107-13
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Tidskriftsartikel (refereegranskat)abstract
- DNA hypermethylation of gene promoters is a common epigenetic alteration occurring in cancer cells. However, little is known about the mechanisms instructing these cancer-specific DNA hypermethylation events. Recent reports have suggested that genes bound by polycomb/Histone H3 lysine 27 trimethylation (H3K27me3) in embryonic stem (ES) cells are frequent targets for cancer-specific DNA hypermethylation. This polycomb-premarking is assumed to be restrained to ES cells, even though almost no polycomb/H3K27me3 binding profiles are available for differentiated tissues. We generated H3K27me3 profiles in human normal colon and they significantly overlapped with those of ES cells and genes hypermethylated in colorectal cancer (CRC). Moreover, colon H3K27me3 was more restricted to genes hypermethylated in CRC, while ES H3K27me3 was also common in genes hypermethylated in other tumors. Therefore, the suggested polycomb pre-marking of genes for cancer DNA hypermethylation is not necessarily limited to ES or early precursor cells but can occur later in differentiated tissues.
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10. |
- Rada-Iglesias, Alvaro, et al.
(författare)
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Whole-genome maps of USF1 and USF2 binding and histone H3 acetylation reveal new aspects of promoter structure and candidate genes for common human disorders
- 2008
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 18:3, s. 380-392
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Tidskriftsartikel (refereegranskat)abstract
- Transcription factors and histone modifications are crucial regulators of gene expression that mutually influence each other. We present the DNA binding profiles of upstream stimulatory factors 1 and 2 (USF1, USF2) and acetylated histone H3 (H3ac) in a liver cell line for the whole human genome using ChIP-chip at a resolution of 35 base pairs. We determined that these three proteins bind mostly in proximity of protein coding genes transcription start sites (TSSs), and their bindings are positively correlated with gene expression levels. Based on the spatial and functional relationship between USFs and H3ac at protein coding gene promoters, we found similar promoter architecture for known genes and the novel and less-characterized transcripts human mRNAs and spliced ESTs. Furthermore, our analysis revealed a previously underestimated abundance of genes in a bidirectional conformation, where USFs are bound in between TSSs. After taking into account this promoter conformation, the results indicate that H3ac is mainly located downstream of TSS, and it is at this genomic location where it positively correlates with gene expression. Finally, USF1, which is associated to familial combined hyperlipidemia, was found to bind and potentially regulate nuclear mitochondrial genes as well as genes for lipid and cholesterol metabolism, frequently in collaboration with GA binding protein transcription factor alpha (GABPA, nuclear respiratory factor 2 [NRF-2]). This expands our understanding about the transcriptional control of metabolic processes and its alteration in metabolic disorders.
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