| 11. |
- 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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| 12. |
- 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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| 13. |
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| 14. |
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| 15. |
- Enroth, Stefan, et al.
(författare)
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Prevalence and sensitization of atopic allergy and coeliac disease in the Northern Sweden Population Health Study
- 2013
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Ingår i: International Journal of Circumpolar Health. - : Informa UK Limited. - 1239-9736 .- 2242-3982. ; 72, s. 21403-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND:Atopic allergy is effected by a number of environmental exposures, such as dry air and time spent outdoors, but there are few estimates of the prevalence in populations from sub-arctic areas.OBJECTIVE:To determine the prevalence and severity of symptoms of food, inhalation and skin-related allergens and coeliac disease (CD) in the sub-arctic region of Sweden. To study the correlation between self-reported allergy and allergy test results. To estimate the heritability of these estimates.STUDY DESIGN:The study was conducted in Karesuando and Soppero in Northern Sweden as part of the Northern Sweden Population Health Study (n=1,068). We used a questionnaire for self-reported allergy and CD status and measured inhalation-related allergens using Phadiatop, food-related allergens using the F×5 assay and IgA and IgG antibodies against tissue transglutaminase (anti-tTG) to indicate prevalence of CD.RESULTS:The prevalence of self-reported allergy was very high, with 42.3% reporting mild to severe allergy. Inhalation-related allergy was reported in 26.7%, food-related allergy in 24.9% and skin-related allergy in 2.4% of the participants. Of inhalation-related allergy, 11.0% reported reactions against fur and 14.6% against pollen/grass. Among food-related reactions, 14.9% reported milk (protein and lactose) as the cause. The IgE measurements showed that 18.4% had elevated values for inhalation allergens and 11.7% for food allergens. Self-reported allergies and symptoms were positively correlated (p<0.01) with age- and sex-corrected inhalation allergens. Allergy prevalence was inversely correlated with age and number of hours spent outdoors. High levels of IgA and IgG anti-tTG antibodies, CD-related allergens, were found in 1.4 and 0.6% of participants, respectively. All allergens were found to be significantly (p<3 e-10) heritable, with estimated heritabilities ranging from 0.34 (F×5) to 0.65 (IgA).CONCLUSIONS:Self-reported allergy correlated well with the antibody measurements. The prevalence of allergy was highest in the young and those working inside. Heritability of atopy and sensitization was high. The prevalence of CD-related autoantibodies was high and did not coincide with the self-reported allergy.
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| 16. |
- 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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| 17. |
- 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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| 18. |
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| 19. |
- Johanneson, Bo, et al.
(författare)
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Systematic validation of hypothesis-driven candidate genes for cervical cancer in a genome-wide association study
- 2014
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Ingår i: Carcinogenesis. - : Oxford University Press (OUP). - 0143-3334 .- 1460-2180. ; 35:9, s. 2084-2088
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Tidskriftsartikel (refereegranskat)abstract
- A large number of genetic associations with cervical cancer have been reported in hypothesis-driven candidate gene studies, but most studies have not included an independent replication or the results have been inconsistent between studies. In order to independently validate these associations, we re-examined 58 candidate gene/regions previously reported to be associated with cervical cancer using the gene-based Adaptive Rank Truncated Product (ARTP) test in a genome-wide association study of 1,034 cervical cancer patients and 3,948 controls from the Swedish population. Of the 58 gene/regions, 8 had a nominal p-value < 0.05 (Tumor necrosis factor [TNF], p = 5.0×10(-4); DEAD (Asp-Glu-Ala-Asp) box helicase 1 [DDX1], p = 2.2×10(-3); Exonuclease 1 [EXO1], p=4.7×10(-3); Excision repair cross-complementing rodent repair deficiency, complementation group 1 [ERCC1], p = 0.020; Transmembrane channel-like 6 and 8 genes [TMC6-TMC8], p = 0.023; Secreted phosphoprotein 1 [SPP1], p= 0.028; v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2], p = 0.033 and Chloride channel, voltage-sensitive 7 [CLCN7], p = 0.047). After correction for multiple testing only TNF remained statistically significant (p = 0.028). Two single-nucleotide polymorphisms that are in nearly perfect linkage disequilibrium (LD) (rs2857602 and rs2844484) contributed most to the association with TNF. However, they are not independent from the previously reported associations within the MHC region. The very low number of previously reported associations with cervical cancer that replicate in the Swedish population underscore the need to apply more stringent criteria when reporting associations, including the prerequisite of replicating the association as part of the original study.
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| 20. |
- Johansson, Åsa, et al.
(författare)
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Continuous Aging of the Human DNA Methylome Throughout the Human Lifespan
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 8:6, s. e67378-
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Tidskriftsartikel (refereegranskat)abstract
- DNA methylation plays an important role in development of disease and the process of aging. In this study we examine DNA methylation at 476,366 sites throughout the genome of white blood cells from a population cohort (N = 421) ranging in age from 14 to 94 years old. Age affects DNA methylation at almost one third (29%) of the sites (Bonferroni adjusted P-value <0.05), of which 60.5% becomes hypomethylated and 39.5% hypermethylated with increasing age. DNA methylation sites that are located within CpG islands (CGIs) more often become hypermethylated compared to sites outside an island. CpG sites in promoters are more unaffected by age, whereas sites in enhancers more often becomes hypo- or hypermethylated. Hypermethylated sites are overrepresented among genes that are involved in DNA binding, transcription regulation, processes of anatomical structure and developmental process and cortex neuron differentiation (P-value down to P = 9.14*10−67). By contrast, hypomethylated sites are not strongly overrepresented among any biological function or process. Our results indicate that the 23% of the variation in DNA methylation is attributed chronological age, and that hypermethylation is more site-specific than hypomethylation. It appears that the change in DNA methylation partly overlap with regions that change histone modifications with age, indicating an interaction between the two major epigenetic mechanisms. Epigenetic modifications and change in gene expression over time most likely reflects the natural process of aging and variation between individuals might contribute to the development of age-related phenotypes and diseases such as type II diabetes, autoimmune and cardiovascular disease.
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