Author
Delphine Fradin
Other affiliations: French Institute of Health and Medical Research, Johns Hopkins University School of Medicine, University of Paris-Sud ...read more
Bio: Delphine Fradin is an academic researcher from University of Nantes. The author has contributed to research in topics: DNA methylation & Epigenetics. The author has an hindex of 16, co-authored 37 publications receiving 1038 citations. Previous affiliations of Delphine Fradin include French Institute of Health and Medical Research & Johns Hopkins University School of Medicine.
Topics: DNA methylation, Epigenetics, Methylation, Medicine, Cancer
Papers
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TL;DR: A genome-scale, gene-specific analysis of DNA methylation in the same individuals over a decade apart identifies a personalized epigenomic signature that may correlate with a common genetic trait.
Abstract: The epigenome consists of non–sequence-based modifications, such as DNA methylation, that are heritable during cell division and that may affect normal phenotypes and predisposition to disease. Here, we have performed an unbiased genome-scale analysis of ~4 million CpG sites in 74 individuals with comprehensive array-based relative methylation (CHARM) analysis. We found 227 regions that showed extreme interindividual variability [variably methylated regions (VMRs)] across the genome, which are enriched for developmental genes based on Gene Ontology analysis. Furthermore, half of these VMRs were stable within individuals over an average of 11 years, and these VMRs defined a personalized epigenomic signature. Four of these VMRs showed covariation with body mass index consistently at two study visits and were located in or near genes previously implicated in regulating body weight or diabetes. This work suggests an epigenetic strategy for identifying patients at risk of common disease.
315 citations
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TL;DR: It is demonstrated that XPG endonuclease promotes DNA breaks and DNA demethylation at promoters allowing the recruitment of CTCF and gene looping, which is further stabilized by XPF.
109 citations
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TL;DR: The observation of a CpG-specific, locus-specific methylation pattern, although it can provide an epigenetic biomarker of a multifactorial disease, does not indicate whether the reported epigenetic pattern preexists or follows the establishment of T1D.
Abstract: The insulin (INS) region is the second most important locus associated with Type 1 Diabetes (T1D). The study of the DNA methylation pattern of the 7 CpGs proximal to the TSS in the INS gene promoter revealed that T1D patients have a lower level of methylation of CpG -19, -135 and -234 (p = 2.10(-16)) and a higher methylation of CpG -180 than controls, while methylation was comparable for CpG -69, -102, -206. The magnitude of the hypomethylation relative to a control population was 8-15% of the corresponding levels in controls and was correlated in CpGs -19 and -135 (r = 0.77) and CpG -135 and -234 (r = 0.65). 70/485 (14%) of T1D patients had a simultaneous decrease in methylation of CpG -19, -135, -234 versus none in 317 controls. CpG methylation did not correlate with glycated hemoglobin or with T1D duration. The methylation of CpG -69, -102, -180, -206, but not CpG -19, -135, -234 was strongly influenced by the cis-genotype at rs689, a SNP known to show a strong association with T1D. We hypothesize that part of this genetic association could in fact be mediated at the statistical and functional level by the underlying changes in neighboring CpG methylation. Our observation of a CpG-specific, locus-specific methylation pattern, although it can provide an epigenetic biomarker of a multifactorial disease, does not indicate whether the reported epigenetic pattern preexists or follows the establishment of T1D. To explore the effect of chronic hyperglycemia on CpG methylation, we studied non obese patients with type 2 diabetes (T2D) who were found to have decreased CpG-19 methylation versus age-matched controls, similar to T1D (p = 2.10(-6)) but increased CpG-234 methylation (p = 5.10(-8)), the opposite of T1D. The causality and natural history of the different epigenetic changes associated with T1D or T2D remain to be determined.
90 citations
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TL;DR: It is demonstrated that CD8+ T cells internalize exosomes from different tumor types even if these cells do not internalize vesicles as readily as other immune cells, and suggested that miRNAs in melanoma-derived exosome aid tumor immune evasion and could be a therapeutic target.
Abstract: MicroRNAs (miRNA), small noncoding RNAs that regulate gene expression, exist not only in cells but also in a variety of body fluids. These circulating miRNAs could enable intercellular communication. miRNAs are packaged in membrane-encapsulated vesicles, such as exosomes, or protected by RNA-binding proteins. Here, we report that miRNAs included in human melanoma exosomes regulate the tumor immune response. Using microscopy and flow cytometry, we demonstrate that CD8+ T cells internalize exosomes from different tumor types even if these cells do not internalize vesicles as readily as other immune cells. We explored the function of melanoma-derived exosomes in CD8+ T cells and showed that these exosomes downregulate T-cell responses through decreased T-cell receptor (TCR) signaling and diminished cytokine and granzyme B secretions. The result reduces the cells' cytotoxic activity. Using mimics, we found that miRNAs enriched in exosomes-such as Homo sapiens (hsa)-miR-3187-3p, hsa-miR-498, hsa-miR-122, hsa-miR149, and hsa-miR-181a/b-regulate TCR signaling and TNFα secretion. Our observations suggest that miRNAs in melanoma-derived exosomes aid tumor immune evasion and could be a therapeutic target.
83 citations
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TL;DR: These regions may harbor imprinted sites associated with the development of autism and offer fruitful domains for molecular investigation into the role of epigenetic mechanisms in autism.
Abstract: Background: Autism is a common heritable neurodevelopmental disorder with complex etiology. Several genome-wide linkage and association scans have been carried out to identify regions harboring genes related to autism or autism spectrum disorders, with mixed results. Given the overlap in autism features with genetic abnormalities known to be associated with imprinting, one possible reason for lack of consistency would be the influence of parent-of-origin effects that may mask the ability to detect linkage and association. Methods and Findings: We have performed a genome-wide linkage scan that accounts for potential parent-of-origin effects using 16,311 SNPs among families from the Autism Genetic Resource Exchange (AGRE) and the National Institute of Mental Health (NIMH) autism repository. We report parametric (GH, Genehunter) and allele-sharing linkage (Aspex) results using a broad spectrum disorder case definition. Paternal-origin genome-wide statistically significant linkage was observed on chromosomes 4 (LODGH=3.79, empirical p,0.005 and LODAspex=2.96, p=0.008), 15 (LODGH=3.09, empirical p,0.005 and LODAspex=3.62, empirical p=0.003) and 20 (LODGH=3.36, empirical p,0.005 and LODAspex=3.38, empirical p=0.006). Conclusions: These regions may harbor imprinted sites associated with the development of autism and offer fruitful domains for molecular investigation into the role of epigenetic mechanisms in autism.
59 citations
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TL;DR: A quantitative model of aging is built using measurements at more than 450,000 CpG markers from the whole blood of 656 human individuals, aged 19 to 101, to measure the rate at which an individual's methylome ages, which is impacted by gender and genetic variants.
2,430 citations
01 Jan 2010
TL;DR: In this paper, the authors show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait, revealing patterns with important implications for genetic studies of common human diseases and traits.
Abstract: Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
1,751 citations
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1,217 citations
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TL;DR: In this paper, the authors introduce a method to create interslice image shifts in the phase encoding direction to increase the distance between aliasing pixels, induced using sign-and amplitude-modulated slice-select gradient blips simultaneous with the EPI phase encoding blips.
Abstract: Simultaneous multislice Echo Planar Imaging (EPI) acquisition using parallel imaging can decrease the acquisition time for diffusion imaging and allow full-brain, high-resolution functional MRI (fMRI) acquisitions at a reduced repetition time (TR) However, the unaliasing of simultaneously acquired, closely spaced slices can be difficult, leading to a high g-factor penalty We introduce a method to create interslice image shifts in the phase encoding direction to increase the distance between aliasing pixels The shift between the slices is induced using sign- and amplitude-modulated slice-select gradient blips simultaneous with the EPI phase encoding blips This achieves the desired shifts but avoids an undesired "tilted voxel" blurring artifact associated with previous methods We validate the method in 3× slice-accelerated spin-echo and gradient-echo EPI at 3 T and 7 T using 32-channel radio frequency (RF) coil brain arrays The Monte-Carlo simulated average g-factor penalty of the 3-fold slice-accelerated acquisition with interslice shifts is <1% at 3 T (compared with 32% without slice shift) Combining 3× slice acceleration with 2× inplane acceleration, the g-factor penalty becomes 19% at 3 T and 10% at 7 T (compared with 41% and 23% without slice shift) We demonstrate the potential of the method for accelerating diffusion imaging by comparing the fiber orientation uncertainty, where the 3-fold faster acquisition showed no noticeable degradation
1,183 citations
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TL;DR: This work discusses EWAS design, cohort and sample selections, statistical significance and power, confounding factors and follow-up studies, and how integration of EWASs with GWASs can help to dissect complex GWAS haplotypes for functional analysis.
Abstract: Despite the success of genome-wide association studies (GWASs) in identifying loci associated with common diseases, a substantial proportion of the causality remains unexplained. Recent advances in genomic technologies have placed us in a position to initiate large-scale studies of human disease-associated epigenetic variation, specifically variation in DNA methylation. Such epigenome-wide association studies (EWASs) present novel opportunities but also create new challenges that are not encountered in GWASs. We discuss EWAS design, cohort and sample selections, statistical significance and power, confounding factors and follow-up studies. We also discuss how integration of EWASs with GWASs can help to dissect complex GWAS haplotypes for functional analysis.
1,163 citations