| 1. |
- Alkema, WBL, et al.
(författare)
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Regulog analysis: detection of conserved regulatory networks across bacteria: application to Staphylococcus aureus
- 2004
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1088-9051. ; 14:7, s. 1362-1373
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Tidskriftsartikel (refereegranskat)abstract
- A transcriptional regulatory network encompasses sets of genes (regulons) whose expression states are directly altered in response to an activating signal, mediated by trans-acting regulatory proteins and cis-acting regulatory sequences. Enumeration of these network components is an essential step toward the creation of a framework for systems-based analysis of biological processes. Profile-based methods for the detection of cis-regulatory elements are often applied to predict regulon members, but they suffer from poor specificity. In this report we describe Regulogger, a novel computational method that uses comparative genomics to eliminate spurious members of predicted gene regulons. Regulogger produces regulogs, sets of coregulated genes for which the regulatory sequence has been conserved across multiple organisms. The quantitative method assigns a confidence score to each predicted regulog member on the basis of the degree of conservation of protein sequence and regulatory mechanisms. When applied to a reference collection of regulons from Escherichia coli, Regulogger increased the specificity of predictions up to 25-fold over methods that use cis-element detection in isolation. The enhanced specificity was observed across a wide range of biologically meaningful parameter combinations, indicating a robust and broad utility for the method. The power of computational pattern discovery methods coupled with Regulogger to unravel transcriptional networks was demonstrated in an analysis of the genome of Staphylococcus aureus. A total of 125 regulogs were found in this organism, including both well-defined functional groups and a subset with unknown functions.
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| 5. |
- Forrest, ARR, et al.
(författare)
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A promoter-level mammalian expression atlas
- 2014
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 507:7493, s. 462-
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Tidskriftsartikel (refereegranskat)
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| 6. |
- Grapotte, M, et al.
(författare)
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Discovery of widespread transcription initiation at microsatellites predictable by sequence-based deep neural network
- 2021
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 12:1, s. 3297-
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Tidskriftsartikel (refereegranskat)abstract
- Using the Cap Analysis of Gene Expression (CAGE) technology, the FANTOM5 consortium provided one of the most comprehensive maps of transcription start sites (TSSs) in several species. Strikingly, ~72% of them could not be assigned to a specific gene and initiate at unconventional regions, outside promoters or enhancers. Here, we probe these unassigned TSSs and show that, in all species studied, a significant fraction of CAGE peaks initiate at microsatellites, also called short tandem repeats (STRs). To confirm this transcription, we develop Cap Trap RNA-seq, a technology which combines cap trapping and long read MinION sequencing. We train sequence-based deep learning models able to predict CAGE signal at STRs with high accuracy. These models unveil the importance of STR surrounding sequences not only to distinguish STR classes, but also to predict the level of transcription initiation. Importantly, genetic variants linked to human diseases are preferentially found at STRs with high transcription initiation level, supporting the biological and clinical relevance of transcription initiation at STRs. Together, our results extend the repertoire of non-coding transcription associated with DNA tandem repeats and complexify STR polymorphism.
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| 7. |
- Ha, TJ, et al.
(författare)
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Identification of novel cerebellar developmental transcriptional regulators with motif activity analysis
- 2019
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Ingår i: BMC genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 20:1, s. 718-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe work of the FANTOM5 Consortium has brought forth a new level of understanding of the regulation of gene transcription and the cellular processes involved in creating diversity of cell types. In this study, we extended the analysis of the FANTOM5 Cap Analysis of Gene Expression (CAGE) transcriptome data to focus on understanding the genetic regulators involved in mouse cerebellar development.ResultsWe used the HeliScopeCAGE library sequencing on cerebellar samples over 8 embryonic and 4 early postnatal times. This study showcases temporal expression pattern changes during cerebellar development. Through a bioinformatics analysis that focused on transcription factors, their promoters and binding sites, we identified genes that appear as strong candidates for involvement in cerebellar development. We selected several candidate transcriptional regulators for validation experiments including qRT-PCR and shRNA transcript knockdown. We observed marked and reproducible developmental defects in Atf4, Rfx3, and Scrt2 knockdown embryos, which support the role of these genes in cerebellar development.ConclusionsThe successful identification of these novel gene regulators in cerebellar development demonstrates that the FANTOM5 cerebellum time series is a high-quality transcriptome database for functional investigation of gene regulatory networks in cerebellar development.
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| 11. |
- Klein, S, et al.
(författare)
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DeepCAGE transcriptomics identify HOXD10 as a transcription factor regulating lymphatic endothelial responses to VEGF-C
- 2016
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Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 129:13, s. 2573-2585
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Tidskriftsartikel (refereegranskat)abstract
- Lymphangiogenesis plays a crucial role during development, in cancer metastasis and in inflammation. Activation of VEGFR-3 by VEGF-C is one of the main drivers of lymphangiogenesis, but the transcriptional events downstream of VEGFR-3 activation are largely unknown. Recently, we identified a wave of immediate early transcription factors (TF) upregulated in human lymphatic endothelial cells (LEC) within the first 30 to 80 min after VEGFR-3 activation. Expression of these TFs must be regulated by additional, pre-existing TFs, which are rapidly activated by VEGFR-3 signaling. Using TF activity analysis, we identified the homeobox TF HOXD10 to be specifically activated at early time points after VEGFR-3 stimulation, and to regulate expression of immediate early TFs, including NR4A1. Gain- and loss of function studies revealed that HOXD10 is involved in LEC migration and formation of cord-like structures. Furthermore, HOXD10 regulates expression of VE-cadherin, claudin-5 and e-NOS, and promotes lymphatic endothelial permeability. Taken together, these results reveal an important and unanticipated role of HOXD10 in the regulation of VEGFR-3 signaling in lymphatic endothelial cells and in the control of lymphangiogenesis and permeability.
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| 12. |
- Krivan, W, et al.
(författare)
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A predictive model for regulatory sequences directing liver-specific transcription
- 2001
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 11:9, s. 1559-1566
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Tidskriftsartikel (refereegranskat)abstract
- The identification and interpretation of the regulatory signals within the human genome remain among the greatest goals and most difficult challenges in genome analysis. The ability to predict the temporal and spatial control of transcription is likely to require a combination of methods to address the contribution of sequence-specific signals, protein–protein interactions and chromatin structure. We present here a new procedure to identify clusters of transcription factor binding sites characteristic of sequence modules experimentally verified to direct transcription selectively to liver cells. This algorithm is sufficiently specific to identify known regulatory sequences in genes selectively expressed in liver, promising acceleration of experimental promoter analysis. In combination with phylogenetic footprinting, this improvement in the specificity of predictions is sufficient to motivate a scan of the human genome. Potential regulatory modules were identified in orthologous human and rodent genomic sequences containing both known and uncharacterized genes.[Supplementary data and the submission of sequences for analysis are available athttp://www.cgb.ki.se/krivan/liver/liver.html.]
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| 13. |
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| 14. |
- Lenhard, B, et al.
(författare)
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GeneLynx: a gene-centric portal to the human genome
- 2001
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 11:12, s. 2151-2157
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Tidskriftsartikel (refereegranskat)abstract
- GeneLynx is a meta-database providing an extensive collection of hyperlinks to human gene-specific information in diverse databases available on the Internet. The GeneLynx project is based on the simple notion that given any gene-specific identifier (accession number, gene name, text, or sequence), scientists should be able to access a single location that provides a set of links to all the publicly available information pertinent to the specified human gene. GeneLynx was implemented as an extensible relational database with an intuitive and user-friendly Web interface. The data are automatically extracted from more than 40 external resources, using appropriate approaches to maximize coverage of the available data. Construction and curation of the system is mediated by a custom set of software tools. An indexing utility is provided to facilitate the establishment of hyperlinks in external databases. A unique feature of the GeneLynx system is a communal curation system for user-aided annotation. GeneLynx can be accessed freely at http://www.genelynx.org.
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| 15. |
- Lenhard, B, et al.
(författare)
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GeneLynx mouse: integrated portal to the mouse genome
- 2003
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Ingår i: Genome research. - : Cold Spring Harbor Laboratory. - 1088-9051. ; 13:6B, s. 1501-1504
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Tidskriftsartikel (refereegranskat)abstract
- GeneLynx Mouse is a meta-database providing an extensive collection of hyperlinks to mouse gene-specific information in diverse databases available via the Internet. The GeneLynx project is based on the simple notion that given any gene-specific identifier (e.g., accession number, gene name, text, or sequence), scientists should be able to access a single location that provides a set of links to all the publicly available information pertinent to the specified gene. The recent climax in the mouse genome and RIKEN cDNA sequencing projects provided the data necessary for the development of a gene-centric mouse information portal based on the GeneLynx ideals. Clusters of RIKEN cDNA sequences were used to define the initial set of mouse genes. Like its human counterpart, GeneLynx Mouse is designed as an extensible relational database with an intuitive and user-friendly Web interface. Data is automatically extracted from diverse resources, using appropriate approaches to maximize the coverage. To promote cross-database interoperability, an indexing utility is provided to facilitate the establishment of hyperlinks in external databases. As a result of the integration of the human and mouse systems, GeneLynx now serves as a powerful comparative genomics data mining resource. GeneLynx Mouse can be freely accessed at http://mouse.genelynx.org.
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| 22. |
- Yusuf, D, et al.
(författare)
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The transcription factor encyclopedia
- 2012
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Ingår i: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906. ; 13:3, s. R24-
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Tidskriftsartikel (refereegranskat)
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