LATE-REPLICATING HETEROCHROMATIN IS CHARACTERISED BY DECREASED CYTOSINE METHYLATION IN THE HUMAN GENOME
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: John Greally
PROVIDER: E-GEOD-27538 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:Heterochromatin is believed to be associated with increased levels of cytosine methylation. With the recent availability of genome-wide, high-resolution molecular data reflecting cytosine methylation or heterochromatic organization, such relationships can be explored systematically. As a well-defined surrogate for heterochromatin, we tested the relationship between DNA replication timing and cytosine methylation in two human cell types, unexpectedly finding that the later-replicating, more heterochromatic regions to be less methylated than early-replicating regions. When we integrated gene expression data into the study, we found that regions of increased gene expression were earlier replicating, as previously identified, and that transcription-targeted cytosine methylation (TTCM) in gene bodies accounts for the positive correlation with early replication. A Self-Organising Map (SOM) approach was able to identify genomic regions with early replication and increased methylation but lacking annotated transcripts, which would have been missed in simple two variable analyses and may encode unrecognized intergenic transcripts. We conclude that the relationship of cytosine methylation with heterochromatin is not simple, and depends on whether the genomic context is tandemly-repetitive sequences often found near centromeres, which are known to be heterochromatic and methylated, or the remaining majority of the genome, where cytosine methylation is targeted preferentially to the transcriptionally-active, euchromatic compartment of the genome. comparison of human fibroblast and GM06690
2011-08-05 | E-GEOD-27518 | biostudies-arrayexpress
Project description:In lung cancer, hypermethylation of specific gene promoters has been found during the progressive carcinogenesis. The identification of common methylation events will aid in the understanding of molecular events during neoplastic transformation and help develop biomarkers for cancer with high predictive and diagnostic value. To explore common methylation events on a genome-wide scale in lung cancer, we analyzed the methylation profiles of paired NSCLC tumor and far adjacent non-tumor samples using the HELP-microarray assay, which yields information on 1.2 million fragments throughout the genome. In this study, 24 pairs of tumor and adjacent non-tumor samples were analyzed using the HELP assay. At p = 5E-6, we identified 26,138 differentially methylated fragments (corresponding to 2 CpG sites each) in tumor versus non-tumor. The overall trend was consistent with genome-wide hypomethylation and locus specific hypermethylation (localized to CG-island containing promoters). We could identify both known and novel regions of the genome as well as specific gene-promoters that are hypermethylated in tumor versus non-tumor. The HELPassay: HpaII tiny fragment enrichment by ligation-mediated polymerase chain reaction [PCR] assay 24 pairs of NSCLC subjects, tumor and paired non-tumor samples from each subject were analyzed. Individual HpaII restriction digest profiles were compared to an internal MspI digest control, to yield differentially methylated fragments for every sample. Samples were compared intra-subject between tumor and adjacent non-tumor for these differential methylation profiles and the overall significant changes across 24 subjects were identified.
2012-03-31 | E-GEOD-35520 | biostudies-arrayexpress
Project description:Heterochromatin is believed to be associated with increased levels of cytosine methylation. With the recent availability of genome-wide, high-resolution molecular data reflecting cytosine methylation or heterochromatic organization, such relationships can be explored systematically. As a well-defined surrogate for heterochromatin, we tested the relationship between DNA replication timing and cytosine methylation in two human cell types, unexpectedly finding that the later-replicating, more heterochromatic regions to be less methylated than early-replicating regions. When we integrated gene expression data into the study, we found that regions of increased gene expression were earlier replicating, as previously identified, and that transcription-targeted cytosine methylation (TTCM) in gene bodies accounts for the positive correlation with early replication. A Self-Organising Map (SOM) approach was able to identify genomic regions with early replication and increased methylation but lacking annotated transcripts, which would have been missed in simple two variable analyses and may encode unrecognized intergenic transcripts. We conclude that the relationship of cytosine methylation with heterochromatin is not simple, and depends on whether the genomic context is tandemly-repetitive sequences often found near centromeres, which are known to be heterochromatic and methylated, or the remaining majority of the genome, where cytosine methylation is targeted preferentially to the transcriptionally-active, euchromatic compartment of the genome.
2011-08-06 | GSE27518 | GEO
Project description:Heterochromatin is believed to be associated with increased levels of cytosine methylation. With the recent availability of genome-wide, high-resolution molecular data reflecting cytosine methylation or heterochromatic organization, such relationships can be explored systematically. As a well-defined surrogate for heterochromatin, we tested the relationship between DNA replication timing and cytosine methylation in two human cell types, unexpectedly finding that the later-replicating, more heterochromatic regions to be less methylated than early-replicating regions. When we integrated gene expression data into the study, we found that regions of increased gene expression were earlier replicating, as previously identified, and that transcription-targeted cytosine methylation (TTCM) in gene bodies accounts for the positive correlation with early replication. A Self-Organising Map (SOM) approach was able to identify genomic regions with early replication and increased methylation but lacking annotated transcripts, which would have been missed in simple two variable analyses and may encode unrecognized intergenic transcripts. We conclude that the relationship of cytosine methylation with heterochromatin is not simple, and depends on whether the genomic context is tandemly-repetitive sequences often found near centromeres, which are known to be heterochromatic and methylated, or the remaining majority of the genome, where cytosine methylation is targeted preferentially to the transcriptionally-active, euchromatic compartment of the genome.
2011-08-06 | GSE27537 | GEO
Project description:LATE-REPLICATING HETEROCHROMATIN IS CHARACTERISED BY DECREASED CYTOSINE METHYLATION IN THE HUMAN GENOME (expression)
| PRJNA141863 | ENA
Project description:Genetic variation amongst individual humans occurs on many different scales, ranging from gross alterations in the human karyotype to single-nucleotide changes. In this manuscript we explore variation on an intermediate scale-particularly insertions, deletions, and inversions affecting from a few thousand to a few million base pairs. We employed a clone-based method to interrogate this intermediate structural variation in eight individuals of diverse geographic ancestry. Our analysis provides a comprehensive overview of the normal pattern of structural variation present in these genomes, refining the location of 1695 structural variants. We find that 50% were seen in more than one individual and that nearly half lay outside regions of the genome previously described as structurally variant. We discover 525 new insertion sequences that are not present in the human reference genome and show that many of these are variable in copy number among individuals. Sequencing of a subset of structural variants reveals considerable locus complexity and provides insights into the different mutational processes that have shaped the human genome. These data provide the first high-resolution sequence-map of human structural variation-an important standard for genotyping platforms and a prelude to future individual genome sequencing projects. Keywords: comparative genomic hybridization The DNA samples are a panel of 8 Hapmap samples, described by E. Eichler et al. (2007, Nature 447, 161-165). This set of 7 female, and one male samples are from from the Coriell Cell Repository, and is comprised of samples from four populations: four Yoruban, two CEPH, one Chinese, and one Japanese. The reference sample, NA15510, is female and also from the Corriel Cell Repository. This sample has been extensively characterized, (for example in Tuzan et al. 2005, Nature Genetics 10, p1038) and has been recommended for use in CNV detection programs to allow meaningful comparison of data between studies (discussed in Scherer, et al. 2007, Nature Genetics Supplement 39: S7-S15). Each of these samples was hybridized in pairs with the reversed labeling polarities. Additionally, 3 self-self control hybridizations were carried out for the reference sample, NA15510, one on each hybridization date.
2008-05-01 | E-GEOD-10008 | biostudies-arrayexpress
Project description:LATE-REPLICATING HETEROCHROMATIN IS CHARACTERISED BY DECREASED CYTOSINE METHYLATION IN THE HUMAN GENOME (HELP assay)
| PRJNA141861 | ENA
Project description:Ethnic differences in human DNA methylation have been shown for a number of CpG sites, but the genome-wide patterns and extent of these differences are unknown. In addition, whether the genetic control of polymorphic DNA methylation is population-specific has not been investigated. Here we measure DNA methylation near the transcription start sites of over 14,000 genes in 180 cell lines derived from one African and one European population. We find population-specific patterns of DNA methylation at over a third of all genes. Furthermore, although the methylation at over a thousand CpG sites is heritable, these heritabilities are also distinctly different between populations, suggesting extensive divergence in the genetic control of DNA methylation. In support of this, genetic mapping of DNA methylation reveals that there is also little overlap in genetic associations between populations. This population-specificity is supported by the patterns of DNA methylation in several hundred brain samples, suggesting it holds in vivo and across tissues. These results suggest that DNA methylation is highly divergent between populations, and that this divergence may be due in large part to complex epistasis or gene x environment interactions. Genomic DNA from 180 lymphoblastoid cell lines were bisulphite converted and hybridized, along with 8 additional technical replicates, to the Illumina Infinium HumanMethylation27 Beadchip v1.2 for genome-wide DNA methylation profiling. The cell lines were derived from two HapMap populations: 'CEPH (Utah residents with ancestry from northern and western Europe)' (CEU) and 'Yoruba in Ibadan, Nigeria' (YRI).
2012-01-30 | E-GEOD-27146 | biostudies-arrayexpress
Project description:Elucidating cytosine modification difference between human populations can enhance our understanding of ethnic specificity in complex traits such as disease predisposition and drug response. In this study, cytosine modification levels in 133 HapMap lymphoblastoid cell lines (LCLs) derived from individuals of European or African ancestry were profiled using the Illumina HumanMethylation450 BeadChip. Approximately 13% of the analyzed CpG sites showed differential modification between the two populations at false discovery rate (FDR) of 1%. CpG sites with greater modification levels in European descents were enriched in the proximal regulatory regions, while those greater in African descents were biased toward gene bodies. More than half of the detected population-specific cytosine modifications could be explained by genetic variation. A substantial proportion of local modification quantitative trait loci (mQTL) exhibited population-specific effects, suggesting that genetic epistasis and/or genotype × environment interaction could be common. Distinct inter-individual correlations were observed between gene expression and cytosine modifications in both proximal promoters and gene bodies, demonstrating a regulatory role of inter-individual variation in cytosine modification. Furthermore, a number of SNPs (single nucleotide polymorphisms) previously identified for complex traits with known racial disparities could be annotated as mQTLs for population-specific CpGs. Our findings revealed abundant population-specific cytosine modifications and the underlying genetic basis, as well as the relatively independent contribution of genetic and epigenetic variations to population differences in gene expression. 60 HapMap CEU and 73 HapMap YRI samples from Coriell Insitute were profiled for cytosine modification levels.
2013-07-01 | E-GEOD-39672 | biostudies-arrayexpress