Validation of differentially methylated DNA regions in colorectal precancerous lesions.
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Illumina NovaSeq 6000
ORGANISM(S): Homo sapiens
SUBMITTER: Mark Robinson
PROVIDER: E-MTAB-12612 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Migration is essential for the reproduction and survival of many animals, yet little is understood about its underlying molecular mechanisms. We used the salmonid Oncorhynchus mykiss to gain mechanistic insight into smoltification, which is a morphological, physiological, and behavioral transition undertaken by some juveniles that culminates in a seaward migration. This species is experimentally tractable and, unlike common model species, displays intra- and inter-population variation in migration propensity. Migratory individuals can produce non-migratory progeny and vice versa, indicating a high degree of phenotypic plasticity. One potential way that phenotypic plasticity might be linked to variation in migration-related life history tactics is through epigenetic regulation of gene expression. To explore this, we quantitatively measured genome-scale DNA methylation in fin tissue using reduced representation bisulfite sequencing of F2 siblings produced from a cross between steelhead (migratory) and rainbow trout (non-migratory) lines. We identified 57 differentially methylated regions (DMRs) between smolt and resident O. mykiss juveniles. DMRs were of high magnitude, ranging from 20-62% differential methylation between life history types, and over half of the gene-associated DMRs were in transcriptional regulatory regions. Many of the DMRs encode proteins with activity relevant to migration-related transitions (e.g. circadian rhythm pathway, nervous system development, protein kinase activity). This study provides the first evidence of a relationship between epigenetic variation and life history divergence associated with a migration-related transition in any species. Comparing global DNA methyldation profiles (via RRBS) of resident and smolt O. mykiss siblings using caudal fin tissue.
2015-06-18 | E-GEOD-62195 | biostudies-arrayexpress
Project description:Bovine tuberculosis (bTB), caused by Mycobacterium bovis, represents a significant issue for the global agriculture industry as well as for human health. Epigenetic modifications can alter the course of the immune response and differentially methylated regions (DMRs) could contribute to the failure of current generation tests to detect all TB-infected cattle. Whole Genome Bisulphite Sequencing (WGBS) was used to profile DNA methylation levels from peripheral blood of cattle naturally infected with M. bovis (positive for the single intradermal comparative tuberculin test (SICTT) and/or the interferon-γ release assay (IGRA) compared to negative controls [n=8/group, total of 16 WGBS libraries]. Although overall methylation profiles were similar across the genome, 224 DMRs and 159 Differentially Methylated Promoter Gene (DMPGs) were identified between groups with an excess of hypermethylated sites in bTB+ infected cattle (threshold >15% differential methylation). Genes located within these DMRs included the Interleukin 1 receptor (IL1R1) and MHC related genes (BOLA and BOLA-DQB) which may influence effective immunity. KEGG pathway analysis identified enrichment of genes involved in Calcium and MAPK signalling, as well as metabolism pathways. Analysis of DMRs in a subset of SICTT- cattle (n=4 group) which were IGRA+, and thereby potentially represent a risk for disease recurrence on farms, showed differential methylation of genes including Interleukin 10 Receptor, alpha (IL10RA), Interleukin 17F (IL17F) and host defence peptides (DEFB and BDEF109). This study has identified a number of immune gene loci at which differential methylation could impact on the host immune response and the ability of cattle to clear infection. Differential methylation of immune gene loci is an informative avenue to improve our understanding of the regulation of host immunity as well as the role of methylation on diagnostic test performance.
2024-06-26 | E-MTAB-13487 | biostudies-arrayexpress
Project description:We propose a statistical algorithm MethylPurify that uses regions with bisulfite reads showing discordant methylation levels to infer tumor purity from tumor samples alone. With purity estimate, MethylPurify can identify differentially methylated regions (DMRs) from individual tumor samples without genomic variation information or prior knowledge from other datasets. In simulations with mixed bisulfite reads from cancer and normal cell lines, MethylPurify correctly inferred tumor purity and identified over 96% of the DMRs. On real patient data where tumor to normal comparison were used as golden standard, MethylPurify called DMR from tumor samples alone at over 57% sensitivity and 91% specificity. Lung adenocarcinoma cancer and normal tissues from 5 patients were captured by Agilent SureSelect Methyl-Seq system, followed by bisulfite sequencing.
2014-07-08 | E-GEOD-56712 | biostudies-arrayexpress
Project description:We report the application of DNA sequencing technology for high-throughput sequencing of mix bis-PCR products totally 38 based on bisulfate treated DNA from human, chimpanzee, gibbon, macaque and crab eating macaque profrontal cortex tissues. Mix bisulfate PCR products from 1 tissues, 23 individula humans, 2 individual chimpanzees, 1 individual gibbons, 7 individual rhesus macaques and 5 crab eating macaques were sequenced by using MiSeq
2016-08-16 | E-GEOD-76788 | biostudies-arrayexpress
Project description:Maternal 5-HT1A-receptor (R) is required for the timely development of the hippocampus and the establishment of emotional behaviors in Swiss-Webster (SW) mice. A partial and/or complete loss of maternal 5-HT1AR results in delayed ventral dentate granule cell (v-DGC) development and subsequent anxiety-like phenotype in the wild-type offspring by a non-genetic, presumably epigenetic mechanism. Here we tested v-DGCs for genome-wide DNA methylation changes elicited by the receptor deficient maternal environment. We identified a set of hypomethylated regions in the offspring of receptor deficient mothers. A significant fraction of these maternal-differentially methylated regions (m-DMRs) mapped to strong CpG islands, sequences that are typically not methylated or if methylated, resistant to environmental-induced changes. Many m-DMRs mapped to exons and some were associated with expression changes. Their hypomethylation was due to an arrest in de novo methylation and, to a lesser extent, to demethylation during postnatal life indicating that the perturbation in methylation coincides with the developmental delay in DGC maturation in the offspring of receptor deficient mothers. Inhibiting methylation in differentiating neurons impaired their maturation further suggesting a link between de novo methylation and neuronal differentiation. These data suggest that methylation at specific exonic CpG-islands may contribute to the mechanism through which maternal 5-HT1AR modulates hippocampal development and consecutively the level of anxiety in the SW offspring. Reduced 5-HT1AR-binding has been reported in individuals, particularly in association with anxiety/depression, including peri/postpartum depression. Therefore, maternal receptor deficit may contribute, via a non-genetic mechanism, to the high prevalence and heritability of anxiety disorders in human. Examined transcriptomes of 5HT1A wild type offspring with 5HT1A wild type/heterozygous mother or 5HT1A KO offspring with 5HT1A of heterozygous/knock out mother
2013-02-04 | E-GEOD-35838 | biostudies-arrayexpress
Project description:Background: Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood. Results: Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T-lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in brain cells. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites, implicating a mechanism involving altered transcription factor binding. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects. Conclusions: These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning. Examination of methylation changes in two mouse models of Down syndrome with sub-chromosomal duplications, Dp(10)1Yey and Dp(16)1Yey, compared to one littermate wild type mouse using whole genome bisulfite sequencing.
2015-10-30 | E-GEOD-74505 | biostudies-arrayexpress
Project description:Myelodysplastic syndromes and chronic myelomonocytic leukemia (CMML) are characterized by mutations in epigenetic modifiers and aberrant DNA methylation. DNA methyltransferase inhibitors (DMTis) are used to treat these disorders, but response is highly variable with few means to predict which patients will benefit. To develop a molecular means of predicting response at diagnosis, we examined baseline differences in mutations, DNA methylation, and gene expression in 40 CMML patients responsive and resistant to decitabine (DAC). While somatic mutations did not differentiate responders and non-responders, we were able to identify for the first time 158 differentially methylated regions (DMRs) at baseline between responders and non-responders using next-generation sequencing. These DMRs were primarily localized to non-promoter regions and overlapped with distal regulatory enhancers. Using the methylation profiles, we developed an epigenetic classifier that accurately predicted DAC response at the time of diagnosis. We also found 53 differentially expressed genes between responders and non-responders. Genes up-regulated in responders were enriched in the cell cycle, potentially contributing to effective DAC incorporation. Two chemokines overexpressed in non-responders -- CXCL4 and CXCL7 -- were able to block the effect of DAC on normal CD34+ and primary CMML cells in vitro, suggesting their up-regulation contributes to primary DAC resistance. DNA methylation profiling in bone marrow mononuclear cells (BM MNC) from 39 CMML patients (19 decitabine responders vs. 20 non-responders).
2015-03-31 | E-GEOD-61161 | biostudies-arrayexpress
Project description:Chronic lymphocytic leukemia (CLL) is a biologically and clinically heterogeneous disease. The somatic hypermutation status of the immunoglobulin heavy chain variable (IGHV) genes has been identified as one of the most robust prognostic markers in CLL. Patients with unmutated IGHV status (U-CLL) typically experience an inferior outcome compared to those whose clones express mutated IGHV genes (M-CLL). We conducted a genome-wide DNA methylation analysis in CD19+ B-cells from a group of 43 CLL patients using reduced representation bisulfite sequencing (RRBS). Using base-pair resolution methylation sequencing, 2323 differentially methylated regions between CLL and normal B-cells (CLL-specific DMRs) and 569 between M-CLL and U-CLL samples (IGHV-specific DMRs) were identified in the CLL genomes. The IGHV-specific DMRs are mostly unique when compared to the CLL-specific DMRs. Less than 10% of the IGHV-specific DMRs are located in promoter regions; however, more than half of these overlap with known DNase I hypersensitive sites, enhancer regions marked by histone modification (H3K4Me1 and H3K27Ac), and transcription factor binding sites in the ENCODE datasets, which indicates that these DMRs contain regulatory sequences. Distinctive DNA methylation patterns were observed in M-CLL and U-CLL samples. Overall, U-CLL was found to contain 50% more hypermethylated regions than M-CLL samples. The hypermethylated loci observed in the U-CLL samples also appear to be hypermethylated in normal naïve B-cells as compared memory B-cells, suggesting that M-CLL and U-CLL differ in differentiation status corresponding to normal B-cell differentiation stages. RNA-seq analysis performed using matched samples (n=34), in which both DNA methylation and gene expression data were available, demonstrated excellent correlation between DNA methylation and gene expression. Several genes whose expression status was previously shown to be associated with CLL prognosis such as ZAP70, CRY1, LDOC1, SEPT10, LAG3, and LPL were differentially methylated in the promoter regions between M-CLL and U-CLL samples indicating that DNA methylation plays an important role in defining the gene expression patterns of these prognostic genes. We further validated 9 genes with IGHV-specific DMRs in the promoter regions using bisulfite pyrosequencing, and the results demonstrated excellent correlation between differential methylation and IGHV mutation status. These novel differentially methylated genes could be developed into biomarkers for CLL prognosis. In addition, DNA hypomethylation was observed in a significant number of genes involved in lymphocyte activation such as PDCD1, NFAT1, and CD5. DNA hypomethylation was observed in the proximal promoter and far up-stream enhancer regions of CD5, an important cell surface marker that uniquely identifies CLL. Overall, the DNA methylation landscape in CLL patients indicates that CLL B cells possess an active B-cell phenotype; at the same time, U-CLL and M-CLL are faithfully committed to their lineage resembling either naïve or memory B-cells. In summary, this comprehensive DNA methylation analysis has identified a large number of novel epigenetic changes in CLL patients. The results from this study will further advance our understanding of the epigenetic contribution to molecular subtypes in CLL. To perform a transcriptome analysis in CLL, we generated sequencing libraries from total RNA isolated from purified B-cells of CLL patients and healthy donnors. The RNA-seq libraries were sequenced using Illumina HiSeq2000 sequencer with a read length of 100bp. 11 CLL B-cell samples, 3 normal control samples including one each of normal CD19+ B cells were studied. We generated 20-30 million Illumina sequencing reads for each sample.
2015-02-21 | E-GEOD-66117 | biostudies-arrayexpress
Project description:Clinical exome sequencing of cells freshly isolated from 12 human colorectal carcinoma patients (tumor endothelial cells, normal colon endothelial cells, PBMCs, each n=12) in comparison to DNA isolated from microdissected tumor cells (n=11) from corresponding FFPE-tissue blocks
2023-05-01 | E-MTAB-10521 | biostudies-arrayexpress
Project description:Aberrant CpG methylation is a universal trait of cancer cell genomes and can result in epigenetic modulation of gene activity; however, at which stages tumour-specific epigenetic patterns arise is unknown. Here, we analyse the methylome of APCM in mouse intestinal adenoma as a model of intestinal cancer initiation, and inventory a map of over 13,000 adenoma-specific recurrent differentially methylated regions (DMRs). We find that multiple genes coding for Polycomb proteins are upregulated in adenoma, and concomitantly, hypermethylated DMRs form preferentially at Polycomb target sites. We establish that DMRs are absent from proliferating intestinal epithelial cells or intestinal stem cells, and thus arise de novo after loss of APC. Importantly, a core set of DMRs is conserved in human colon cancer, defining a class of early epigenetic alterations that are distinct from known sets of epigenetically silenced tumour suppressors. The data presented suggests a sequence of events that leads to an altered methylome of colon cancer cells, and may allow more specific selection of clinical epigenetic biomarkers. Analysis of the methylome and RNA expression in adenoma of Apc-Min/+ mutant mice and of normal intestine in Apc-Min/+ and Apc-+/+ wild type mice.
2013-04-03 | E-GEOD-38983 | biostudies-arrayexpress