| 61. |
- 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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| 62. |
- Enroth, Stefan, et al.
(författare)
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A strand specific high resolution normalization method for chip-sequencing data employing multiple experimental control measurements
- 2012
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Ingår i: Algorithms for Molecular Biology. - : Springer Science and Business Media LLC. - 1748-7188. ; 7, s. 2-
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Tidskriftsartikel (refereegranskat)abstract
- Background: High-throughput sequencing is becoming the standard tool for investigating protein-DNA interactions or epigenetic modifications. However, the data generated will always contain noise due to e. g. repetitive regions or non-specific antibody interactions. The noise will appear in the form of a background distribution of reads that must be taken into account in the downstream analysis, for example when detecting enriched regions (peak-calling). Several reported peak-callers can take experimental measurements of background tag distribution into account when analysing a data set. Unfortunately, the background is only used to adjust peak calling and not as a preprocessing step that aims at discerning the signal from the background noise. A normalization procedure that extracts the signal of interest would be of universal use when investigating genomic patterns.Results: We formulated such a normalization method based on linear regression and made a proof-of-concept implementation in R and C++. It was tested on simulated as well as on publicly available ChIP-seq data on binding sites for two transcription factors, MAX and FOXA1 and two control samples, Input and IgG. We applied three different peak-callers to (i) raw (un-normalized) data using statistical background models and (ii) raw data with control samples as background and (iii) normalized data without additional control samples as background. The fraction of called regions containing the expected transcription factor binding motif was largest for the normalized data and evaluation with qPCR data for FOXA1 suggested higher sensitivity and specificity using normalized data over raw data with experimental background.Conclusions: The proposed method can handle several control samples allowing for correction of multiple sources of bias simultaneously. Our evaluation on both synthetic and experimental data suggests that the method is successful in removing background noise.
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| 63. |
- Enroth, Stefan, et al.
(författare)
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Cancer associated epigenetic transitions identified by genome-wide histone methylation binding profiles in human colorectal cancer samples and paired normal mucosa
- 2011
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Ingår i: BMC Cancer. - : BioMed Central. - 1471-2407 .- 1471-2407. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Despite their well-established functional roles, histone modifications have received less attention than DNA methylation in the cancer field. In order to evaluate their importance in colorectal cancer (CRC), we generated the first genome-wide histone modification profiles in paired normal colon mucosa and tumor samples.METHODS: Chromatin immunoprecipitation and microarray hybridization (ChIP-chip) was used to identify promoters enriched for histone H3 trimethylated on lysine 4 (H3K4me3) and lysine 27 (H3K27me3) in paired normal colon mucosa and tumor samples from two CRC patients and for the CRC cell line HT29.RESULTS: By comparing histone modification patterns in normal mucosa and tumors, we found that alterations predicted to have major functional consequences were quite rare. Furthermore, when normal or tumor tissue samples were compared to HT29, high similarities were observed for H3K4me3. However, the differences found for H3K27me3, which is important in determining cellular identity, indicates that cell lines do not represent optimal tissue models. Finally, using public expression data, we uncovered previously unknown changes in CRC expression patterns. Genes positive for H3K4me3 in normal and/or tumor samples, which are typically already active in normal mucosa, became hyperactivated in tumors, while genes with H3K27me3 in normal and/or tumor samples and which are expressed at low levels in normal mucosa, became hypersilenced in tumors.CONCLUSIONS: Genome wide histone modification profiles can be used to find epigenetic aberrations in genes associated with cancer. This strategy gives further insights into the epigenetic contribution to the oncogenic process and may identify new biomarkers.
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| 64. |
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| 65. |
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| 66. |
- Enroth, Stefan, et al.
(författare)
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Combinations of histone modifications mark exon inclusion levels
- 2012
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- Splicing is a complex process regulated by sequence at the classical splice sites and other motifs in exons and introns with an enhancing or silencing effect. In addition, specific histone modifications on nucleosomes positioned over the exons have been shown to correlate both positively and negatively with exon expression. Here, we trained a model of "IF … THEN …" rules to predict exon inclusion levels in a transcript from histone modification patterns. Furthermore, we showed that combinations of histone modifications, in particular those residing on nucleosomes preceding or succeeding the exon, are better predictors of exon inclusion levels than single modifications. The resulting model was evaluated with cross validation and had an average accuracy of 72% for 27% of the exons, which demonstrates that epigenetic signals substantially mark alternative splicing.
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| 67. |
- Enroth, Stefan, et al.
(författare)
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Nucleosome regulatory dynamics in response to TGF beta
- 2014
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Ingår i: Nucleic Acids Research. - : Oxford University Press (OUP). - 0305-1048 .- 1362-4962. ; 42:11, s. 6921-6934
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Tidskriftsartikel (refereegranskat)abstract
- Nucleosomes play important roles in a cell beyond their basal functionality in chromatin compaction. Their placement affects all steps in transcriptional regulation, from transcription factor (TF) binding to messenger ribonucleic acid (mRNA) synthesis. Careful profiling of their locations and dynamics in response to stimuli is important to further our understanding of transcriptional regulation by the state of chromatin. We measured nucleosome occupancy in human hepatic cells before and after treatment with transforming growth factor beta 1 (TGFβ1), using massively parallel sequencing. With a newly developed method, SuMMIt, for precise positioning of nucleosomes we inferred dynamics of the nucleosomal landscape. Distinct nucleosome positioning has previously been described at transcription start site and flanking TF binding sites. We found that the average pattern is present at very few sites and, in case of TF binding, the double peak surrounding the sites is just an artifact of averaging over many loci. We systematically searched for depleted nucleosomes in stimulated cells compared to unstimulated cells and identified 24 318 loci. Depending on genomic annotation, 44-78% of them were over-represented in binding motifs for TFs. Changes in binding affinity were verified for HNF4α by qPCR. Strikingly many of these loci were associated with expression changes, as measured by RNA sequencing.
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| 68. |
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| 69. |
- Enroth, Stefan, 1976-, et al.
(författare)
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SICTIN : Rapid footprinting of massively parallel sequencing data
- 2010
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Ingår i: BioData Mining. - : Springer Science and Business Media LLC. - 1756-0381. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Massively parallel sequencing allows for genome-wide hypothesis-free investigation of for instance transcription factor binding sites or histone modifications. Although nucleotide resolution detailed information can easily be generated, biological insight often requires a more general view of patterns (footprints) over distinct genomic features such as transcription start sites, exons or repetitive regions. The construction of these footprints is however a time consuming task.METHODS: The presented software generates a binary representation of the signals enabling fast and scalable lookup. This representation allows for footprint generation in mere minutes on a desktop computer. Several different input formats are accepted, e.g. the SAM format, bed-files and the UCSC wiggle track.CONCLUSIONS: Hypothesis-free investigation of genome wide interactions allows for biological data mining at a scale never before seen. Until recently, the main focus of analysis of sequencing data has been targeted on signal patterns around transcriptional start sites which are in manageable numbers. Today, focus is shifting to a wider perspective and numerous genomic features are being studied. To this end, we provide a system allowing for fast querying in the order of hundreds of thousands of features.
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| 70. |
- Enroth, Stefan, 1976-
(författare)
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The Nucleosome as a Signal Carrying Unit : From Experimental Data to Combinatorial Models of Transcriptional Control
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The human genome consists of over 3 billion nucleotides and would be around 2 meters long if uncoiled and laid out. Each human somatic cell contains all this in their nucleus which is only around 5 µm across. This extreme compaction is largely achieved by wrapping the DNA around a histone octamer, the nucleosome. Still, the DNA is accessible to the transcriptional machinery and this regulation is highly dynamic and change rapidly with, e.g. exposure to drugs. The individual histone proteins can carry specific modifications such as methylations and acetylations. These modifications are a major part of the epigenetic status of the DNA which contributes significantly to the transcriptional status of a gene - certain modifications repress transcription and others are necessary for transcription to occur. Specific histone methylations and acetylations have also been implicated in more detailed regulation such as inclusion/exclusion of individual exons, i.e. splicing. Thus, the nucleosome is involved in chromatin remodeling and transcriptional regulation – both directly from steric hindrance but also as a signaling platform via the epigenetic modifications. In this work, we have developed tools for storage (Paper I) and normalization (Paper II) of next generation sequencing data in general, and analyzed nucleosome locations and histone modification in particular (Paper I, III and IV). The computational tools developed allowed us as one of the first groups to discover well positioned nucleosomes over internal exons in such wide spread organisms as worm, mouse and human. We have also provided biological insight into how the epigenetic histone modifications can control exon expression in a combinatorial way. This was achieved by applying a Monte Carlo feature selection system in combination with rule based modeling of exon expression. The constructed model was validated on data generated in three additional cell types suggesting a general mechanism.
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