The role of DNA methylation on the organization of the cancer epigenome
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE64929 | GEO | 2015/02/06
SECONDARY ACCESSION(S): PRJNA272524
REPOSITORIES: GEO
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Project description:We assess global chromatin accessibility following high salt wash Simultaneous genome-wide mapping of DNA methylation and nucleosome occupancy of K562 cells
2015-02-06 | E-GEOD-64929 | biostudies-arrayexpress
Project description:The holistic role of DNA methylation in the organization of the cancer epigenome is not well understood. Here we perform a comprehensive, high-resolution analysis of chromatin structure to compare the landscapes of HCT116 colon cancer cells and a DNA methylation-deficient derivative. The NOMe-seq accessibility assay unexpectedly revealed symmetrical and transcription-independent nucleosomal phasing across active, poised, and inactive genomic elements. DNA methylation abolished this phasing primarily at enhancers and CpG island (CGI) promoters, with little effect on insulators and non-CGI promoters. Abolishment of DNA methylation led to the context-specific reestablishment of the poised and active states of normal colon cells, which were marked in methylation-deficient cells by distinct H3K27 modifications and the presence of either well-phased nucleosomes or nucleosome-depleted regions, respectively. At higher-order genomic scales, we found that long, H3K9me3-marked domains had lower accessibility, consistent with a more compact chromatin structure. Taken together, our results demonstrate the nuanced and context-dependent role of DNA methylation in the functional, multiscale organization of cancer epigenomes.
| S-EPMC4381519 | biostudies-literature
Project description:The cytoplasmic functions of Wiskott-Aldrich Syndrome family (WASP) proteins are well known and include roles in cytoskeleton reorganization and membrane-cytoskeletal interactions important for membrane/vesicle trafficking, morphogenesis, immune response and signal transduction. Mis-regulation of these proteins is associated with immune deficiency and metastasis. Cytoplasmic WASP proteins act as effectors of Rho family GTPases and polymerize branched actin through the Arp2/3 complex. However, recent evidence has revealed that this classically cytoplasmic protein family also functions in the nucleus. Previously, we identified Drosophila washout (wash) as a new member of the WASP family with essential cytoplasmic roles in early development. Here we show that Wash is also present in the nucleus and plays a key role in nuclear organization via its interaction with Lamin Dm0 at the nuclear envelope. Wash and Lamin Dm0 occupy similar genomic regions that overlap with transcriptionally silent chromatin including constitutive heterochromatin. Strikingly, wash mutant and knockdown nuclei exhibit the same abnormal wrinkled morphology observed in diverse laminopathies, including the Hutchinson-Gilford progeria syndrome, and consistent with disruption of the nuclear organization of several sub-nuclear structures including cajal bodies and the chromocenter in salivary glands. We also found that Wash and Lamin knockdown disrupt chromatin accessibility of repressive compartments in agreement with an observed global redistribution of repressive histone modifications. Functional genetic approaches show wash mutants exhibit similar phenotypes to lamin Dm0 mutants, suggesting they participate in similar regulatory networks. Our results reveal a novel role for Wash in modulating nuclear organization via its interaction with the nuclear envelope protein Lamin Dm0. These findings highlight the functional complexity of WASP family proteins and provide new venues to understand their molecular roles in cell biology and disease. We evaluated the effect of Wash knockdown in S2R+ cells on chromatin accessibility using an M.SssI-based approach.
2015-03-10 | GSE59852 | GEO
Project description:The cytoplasmic functions of Wiskott-Aldrich Syndrome family (WASP) proteins are well known and include roles in cytoskeleton reorganization and membrane-cytoskeletal interactions important for membrane/vesicle trafficking, morphogenesis, immune response and signal transduction. Mis-regulation of these proteins is associated with immune deficiency and metastasis. Cytoplasmic WASP proteins act as effectors of Rho family GTPases and polymerize branched actin through the Arp2/3 complex. However, recent evidence has revealed that this classically cytoplasmic protein family also functions in the nucleus. Previously, we identified Drosophila washout (wash) as a new member of the WASP family with essential cytoplasmic roles in early development. Here we show that Wash is also present in the nucleus and plays a key role in nuclear organization via its interaction with Lamin Dm0 at the nuclear envelope. Wash and Lamin Dm0 occupy similar genomic regions that overlap with transcriptionally silent chromatin including constitutive heterochromatin. Strikingly, wash mutant and knockdown nuclei exhibit the same abnormal wrinkled morphology observed in diverse laminopathies, including the Hutchinson-Gilford progeria syndrome, and consistent with disruption of the nuclear organization of several sub-nuclear structures including cajal bodies and the chromocenter in salivary glands. We also found that Wash and Lamin knockdown disrupt chromatin accessibility of repressive compartments in agreement with an observed global redistribution of repressive histone modifications. Functional genetic approaches show wash mutants exhibit similar phenotypes to lamin Dm0 mutants, suggesting they participate in similar regulatory networks. Our results reveal a novel role for Wash in modulating nuclear organization via its interaction with the nuclear envelope protein Lamin Dm0. These findings highlight the functional complexity of WASP family proteins and provide new venues to understand their molecular roles in cell biology and disease. DamID chromatin profiling demostrate that Wash binds similar regions to those bound by Lamin Dm0, in particular transcriptional silent chromatin
2015-03-10 | GSE59853 | GEO
Project description:The arrival of the Infinium DNA methylation BeadChips for mice and other nonhuman mammalian species has outpaced the development of the informatics that supports their use for epigenetics study in model organisms. Here, we present informatics infrastructure and methods to allow easy DNA methylation analysis on multiple species, including domesticated animals and inbred laboratory mice (in SeSAMe version 1.16.0+). First, we developed a data-driven analysis pipeline covering species inference, genome-specific data preprocessing and regression modeling. We targeted genomes of 310 species and 37 inbred mouse strains and showed that genome-specific preprocessing prevents artifacts and yields more accurate measurements than generic pipelines. Second, we uncovered the dynamics of the epigenome evolution in different genomic territories and tissue types through comparative analysis. We identified a catalog of inbred mouse strain-specific methylation differences, some of which are linked to the strains' immune, metabolic and neurological phenotypes. By streamlining DNA methylation array analysis for undesigned genomes, our methods extend epigenome research to broad species contexts.
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Project description:In adult patients with obsessive-compulsive disorder (OCD), altered DNA methylation has been discerned in several candidate genes, while DNA methylation on an epigenome-wide level has been investigated in only one Chinese study so far. Here, an epigenome-wide association study (EWAS) was performed in a sample of 76 OCD patients of European ancestry (37 women, age ± SD: 33.51 ± 10.92 years) and 76 sex- and age-matched healthy controls for the first time using the Illumina MethylationEPIC BeadChip. After quality control, nine epigenome-wide significant quantitative trait methylation sites (QTMs) and 21 suggestive hits were discerned in the final sample of 68 patients and 68 controls. The top hit (cg24159721) and four other significant QTMs (cg11894324, cg01070250, cg11330075, cg15174812) map to the region of the microRNA 12136 gene (MIR12136). Two additional significant CpG sites (cg05740793, cg20450977) are located in the flanking region of the MT-RNR2 (humanin) like 8 gene (MT-RNRL8), while two further QTMs (cg16267121, cg15890734) map to the regions of the MT-RNR2 (humanin) like 3 (MT-RNRL3) and MT-RNR2 (humanin) like 2 (MT-RNRL2) genes. Provided replication of the present findings in larger samples, the identified QTMs might provide more biological insight into the pathogenesis of OCD and thereby could in the future serve as peripheral epigenetic markers of OCD risk with the potential to inform targeted preventive and therapeutic efforts.
| S-EPMC9160220 | biostudies-literature
Project description:Understanding the diversity of human tissues is fundamental to disease and requires linking genetic information, which is identical in most of an individual's cells, with epigenetic mechanisms that could have tissue-specific roles. Surveys of DNA methylation in human tissues have established a complex landscape including both tissue-specific and invariant methylation patterns. Here we report high coverage methylomes that catalogue cytosine methylation in all contexts for the major human organ systems, integrated with matched transcriptomes and genomic sequence. By combining these diverse data types with each individuals' phased genome, we identified widespread tissue-specific differential CG methylation (mCG), partially methylated domains, allele-specific methylation and transcription, and the unexpected presence of non-CG methylation (mCH) in almost all human tissues. mCH correlated with tissue-specific functions, and using this mark, we made novel predictions of genes that escape X-chromosome inactivation in specific tissues. Overall, DNA methylation in several genomic contexts varies substantially among human tissues.
| S-EPMC4499021 | biostudies-literature
Project description:PIWI-interacting RNAs (piRNAs) have long been associated with the silencing of transposable elements (TEs). However, over 20,000 unique species of piRNAs mapped to the human genome are more than the relatively few presumably required to regulate the known human transposon classes. Here, we present the results of the first genome-wide effort to study the effects of piRNAs on gene specific DNA methylation. We found that exon-derived piRNAs consist almost universally of species with 10 or fewer genomic copies, whereas piRNAs existing in high copies originate predominately from intronic and intergenic regions. Genome-wide methylation profiling following transfection of human somatic cells with piRNA mimics revealed methylation changes at numerous genic loci in single copy piRNA-transfected cells. Moreover, genomic regions directly adjacent to differentially methylated CpG sites were enriched for sequence matches to the transfected piRNAs. These findings suggest that a subset of single copy piRNAs may be able to induce DNA methylation at non-TE genic loci, a process that may be mediated in part by direct binding to either genomic DNA or nascent mRNA near target CpG sites.
| S-EPMC4615395 | biostudies-literature
Project description:BackgroundEpigenetic mechanisms, including methylation, can contribute to childhood asthma. Identifying DNA methylation profiles in asthmatic patients can inform disease pathogenesis.ObjectiveWe sought to identify differential DNA methylation in newborns and children related to childhood asthma.MethodsWithin the Pregnancy And Childhood Epigenetics consortium, we performed epigenome-wide meta-analyses of school-age asthma in relation to CpG methylation (Illumina450K) in blood measured either in newborns, in prospective analyses, or cross-sectionally in school-aged children. We also identified differentially methylated regions.ResultsIn newborns (8 cohorts, 668 cases), 9 CpGs (and 35 regions) were differentially methylated (epigenome-wide significance, false discovery rate < 0.05) in relation to asthma development. In a cross-sectional meta-analysis of asthma and methylation in children (9 cohorts, 631 cases), we identified 179 CpGs (false discovery rate < 0.05) and 36 differentially methylated regions. In replication studies of methylation in other tissues, most of the 179 CpGs discovered in blood replicated, despite smaller sample sizes, in studies of nasal respiratory epithelium or eosinophils. Pathway analyses highlighted enrichment for asthma-relevant immune processes and overlap in pathways enriched both in newborns and children. Gene expression correlated with methylation at most loci. Functional annotation supports a regulatory effect on gene expression at many asthma-associated CpGs. Several implicated genes are targets for approved or experimental drugs, including IL5RA and KCNH2.ConclusionNovel loci differentially methylated in newborns represent potential biomarkers of risk of asthma by school age. Cross-sectional associations in children can reflect both risk for and effects of disease. Asthma-related differential methylation in blood in children was substantially replicated in eosinophils and respiratory epithelium.
| S-EPMC6556405 | biostudies-literature
Project description:IntroductionDementia pathogenesis begins years before clinical symptom onset, necessitating the understanding of premorbid risk mechanisms. Here we investigated potential pathogenic mechanisms by assessing DNA methylation associations with dementia risk factors in Alzheimer's disease (AD)-free participants.MethodsAssociations between dementia risk measures (family history, AD genetic risk score [GRS], and dementia risk scores [combining lifestyle, demographic, and genetic factors]) and whole-blood DNA methylation were assessed in discovery and replication samples (n = ~400 to ~5000) from Generation Scotland.ResultsAD genetic risk and two dementia risk scores were associated with differential methylation. The GRS associated predominantly with methylation differences in cis but also identified a genomic region implicated in Parkinson disease. Loci associated with dementia risk scores were enriched for those previously associated with body mass index and alcohol consumption.DiscussionDementia risk measures show widespread association with blood-based methylation, generating several hypotheses for assessment by future studies.
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