Rare genetic variation at transcription factor binding site modulates local DNA methylation profiles
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ABSTRACT:
PROVIDER: PRJNA670916 | ENA |
REPOSITORIES: ENA
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Project description:Recently, it has been proposed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Combining blood genome-wide DNA methylation profiles (Illumina Infinium MethylationEPIC BeadChiP), whole genome sequencing-derived single nucleotide variants (SNVs) along with predicted transcription factor binding site (TFBS), we were able to observe that rare regulatory variants, i.e, SNVs that disrupt TFBSs, are associated with DNA methylation at both local and, to a lesser extent, broader locations. Interestingly, we also observed that this directed DNA methylation can have consequences on genome regulation by altering expression levels of nearby genes.
2020-10-24 | GSE159930 | GEO
Project description:Although DNA methylation is the best characterized epigenetic mark, the mechanism by which it is targeted to specific regions in the genome remains unclear. Recent studies have revealed that local DNA methylation profiles might be dictated by cis-regulatory DNA sequences that mainly operate via DNA-binding factors. Consistent with this finding, we have recently shown that disruption of CTCF-binding sites by rare single nucleotide variants (SNVs) can underlie cis-linked DNA methylation changes in patients with congenital anomalies. These data raise the hypothesis that rare genetic variation at transcription factor binding sites (TFBSs) might contribute to local DNA methylation patterning. In this work, by combining blood genome-wide DNA methylation profiles, whole genome sequencing-derived SNVs from 247 unrelated individuals along with 133 predicted TFBS motifs derived from ENCODE ChIP-Seq data, we observed an association between the disruption of binding sites for multiple TFs by rare SNVs and extreme DNA methylation values at both local and, to a lesser extent, distant CpGs. While the majority of these changes affected only single CpGs, 24% were associated with multiple outlier CpGs within ±1kb of the disrupted TFBS. Interestingly, disruption of functionally constrained sites within TF motifs lead to larger DNA methylation changes at nearby CpG sites. Altogether, these findings suggest that rare SNVs at TFBS negatively influence TF-DNA binding, which can lead to an altered local DNA methylation profile. Furthermore, subsequent integration of DNA methylation and RNA-Seq profiles from cardiac tissues enabled us to observe an association between rare SNV-directed DNA methylation and outlier expression of nearby genes. In conclusion, our findings not only provide insights into the effect of rare genetic variation at TFBS on shaping local DNA methylation and its consequences on genome regulation, but also provide a rationale to incorporate DNA methylation data to interpret the functional role of rare variants.
| S-EPMC7679001 | biostudies-literature
Project description:DNA methylation is a chromatin modification that is frequently associated with epigenetic regulation in plants and mammals. However, other genetic changes such as transposon insertions also can lead to changes in DNA methylation levels. Genome-wide profiles of DNA methylation levels for 20 maize inbreds were used to discover differentially methylated regions (DMRs). The methylation level for each of these DMRs was also assayed in 31 additional maize genotypes resulting in the discovery of 1,966 common DMRs and 1,754 rare DMRs. Analysis of recombinant inbred lines provides evidence that the majority of DMRs are heritable. A local association scan found that nearly half of the DMRs with common variation are significantly associated with SNPs found within or near the DMR. Many of the DMRs that are significantly associated with local genetic variation are found near transposable elements that may contribute to the DNA methylation variation. The analysis of gene expression in the same samples used for DNA methylation profiling identifies over 300 genes with expression patterns that are significantly associated with the DNA methylation variation among genotypes. Collectively, our results suggest that DNA methylation variation is influenced by genetic and epigenetic variation is often stably inherited and can influence expression level of genes in the population.
2013-08-12 | GSE46949 | GEO
Project description:DNA methylation is a chromatin modification that is frequently associated with epigenetic regulation in plants and mammals. However, other genetic changes such as transposon insertions also can lead to changes in DNA methylation levels. Genome-wide profiles of DNA methylation levels for 20 maize inbreds were used to discover differentially methylated regions (DMRs). The methylation level for each of these DMRs was also assayed in 31 additional maize genotypes resulting in the discovery of 1,966 common DMRs and 1,754 rare DMRs. Analysis of recombinant inbred lines provides evidence that the majority of DMRs are heritable. A local association scan found that nearly half of the DMRs with common variation are significantly associated with SNPs found within or near the DMR. Many of the DMRs that are significantly associated with local genetic variation are found near transposable elements that may contribute to the DNA methylation variation. The analysis of gene expression in the same samples used for DNA methylation profiling identifies over 300 genes with expression patterns that are significantly associated with the DNA methylation variation among genotypes. Collectively, our results suggest that DNA methylation variation is influenced by genetic and epigenetic variation is often stably inherited and can influence expression level of genes in the population. Methylation profiles in seedling tissue of a panel of 51 maize inbred lines using a custom 2.1M or 1.4M feature NimbleGen array. Methylation profiles in seedling tissue of maize inbred lines, teosinte and recombinant inbred lines (RILs) derived from B73 and Mo17 using a custom 12x270K NimbleGen array. Inbred lines B73 and Mo17 each had 3 biological replicates, the other sample had 1 replicate.
2013-08-12 | E-GEOD-46949 | biostudies-arrayexpress
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Project description:CIDR: The Genetic Basis of Aggressive Prostate Cancer: The Role of Rare Variation
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Project description:A rare chromosome 20 with additional G-positive band was found during prenatal diagnosis. To identified the rare chromosome 20, standard cytogenetic and molecular cytogenetic analysis of the patients was performed. Array comparative genomic hybridization (aCGH) were performed to exclude genomic imbalance.
2016-06-27 | E-MTAB-4755 | biostudies-arrayexpress