Genetic Variants Influence on the Placenta Regulatory Landscape
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ABSTRACT: This study of the regulatory landscape of the placenta relies on the identification of associations between genetic variant and gene expression changes (eQTLs); genetic variant and DNA methylation changes (mQTLs); and, gene expression change and DNA methylation change (eQTMs). It involves the analysis of DNA sequence variation (n=303), DNA methylation (n=303) and mRNA expression data (n=80) from placentas from healthy women. Such studies are crucial to fully apprehend the complexity of the regulatory landscape and to support further analysis focusing and disease driven phenotype.
REPOSITORIES: dbGaP
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Project description:Genetic variants that impact gene regulation are important contributors to human phenotypic variation. For this reason, considerable efforts have been made to identify genetic associations with differences in mRNA levels of nearby genes, namely, cis expression quantitative trait loci (eQTLs). The phenotypic consequences of eQTLs are presumably due, in most cases, to their ultimate effects on protein expression levels. Yet, only few studies have quantified the impact of genetic variation on proteins levels directly. It remains unclear how faithfully eQTLs are reflected at the protein level, and whether there is a significant layer of cis regulatory variation acting primarily on translation or steady state protein levels. To address these questions, we measured ribosome occupancy by high-throughput sequencing, and relative protein levels by high-resolution quantitative mass spectrometry, in a panel of lymphoblastoid cell lines (LCLs) in which we had previously measured transcript expression using RNA sequencing. We then mapped genetic variants that are associated with changes in transcript expression (eQTLs), ribosome occupancy (rQTLs), or protein abundance (pQTLs). Most of the QTLs we detected are associated with transcript expression levels, with consequent effects on ribosome and protein levels. However, we found that eQTLs tend to have significantly reduced effect sizes on protein levels, suggesting that their potential impact on downstream phenotypes is often attenuated or buffered. Additionally, we confirmed the presence of a class of cis QTLs that specifically affect protein abundance with little or no effect on mRNA levels; most of these QTLs have little effect on ribosome occupancy, and hence may arise from differences in post-translational regulation.
2014-12-19 | PXD001406 | Pride
Project description:The impact of genetic regulatory elements on gene expression can change during differentiation and across cell types and environments. We mapped expression quantitative trait loci (eQTLs) throughout differentiation to elucidate the dynamics of genetic effects and the associated cell type specific mechanisms. To do so, we generated high resolution time-series RNA-sequencing data, capturing differentiation from induced pluripotent stem cells to cardiomyocytes with 16 time points in 19 human cell lines. Genetic effects on gene regulation in these data show clear temporal structure. We identified hundreds of dynamic eQTLs that change significantly over time, with enrichment in enhancers of relevant cell types. We also found nonlinear dynamic eQTLs, which have effects only during intermediate stages of differentiation. These include a variant associated with body mass index, highlighting that transient genetic effects can contribute to disease.
2018-11-10 | GSE122380 | GEO
Project description:Studies correlating genetic variation to gene expression facilitate the interpretation of common human phenotypes and disease. As functional variants may be operating in a tissue-dependent manner, we performed gene expression profiling and association with genetic variants (SNPs) on three cell types of 85 individuals. After excluding 10 outlier individuals detected through principal component analysis, we detected cell type-specific genetic effects, with 69 - 80% of regulatory variants operating in a cell type-specific manner and identified multiple eQTLs per gene, unique or shared among cell types and positively correlated with the number of transcripts per gene. Cell type specific eQTLs were found at larger distances from genes and lower effect size similar to known enhancers. These data suggest that the complete regulatory variant repertoire can only be uncovered in the context of cell type specificity.
2009-07-31 | GSE17080 | GEO
Project description:The predominant outcome of cardiovascular disease (CVD) is myocardial infarction (MI), where cardiomyocytes are deprived of oxygen. To study inter-individual differences in cardiomyocytes’ response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We characterized gene expression levels, chromatin accessibility, and methylation profiles in these cardiomyocytes in four culturing conditions that correspond to normoxia (10% O2), hypoxia (1% O2) and short or long-term re-oxygenation (back to 10% O2). In our population sample, 2,113 genes change their expression following hypoxia and short- or long-term re-oxygenation. Using available genotypes from all individuals, we identified 1,573 genes with a cis eQTL in at least one of the four culturing conditions. Taking into account the incomplete power to identify eQTLs in any given condition, we also identified 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of dynamic eQTLs, which are detected only following hypoxia, have not been previously annotated as eQTLs even in much larger collections of heart tissues. We did not detect differences in DNA methylation, or chromatin accessibility as the cells transitioned between normoxia and hypoxia, but we observed a change in chromatin accessibility in 831 genomic regions upon re-oxygenation. Differentially accessible regions are enriched for features of active regulatory regions, SINE elements, and E2F4 transcription factor binding sites . Finally, we found that genes associated with dynamic eQTLs are also associated with complex traits and disease. Our data thus demonstrate how unique genetic effects on gene expression, which are likely relevant for disease, can be uncovered under conditions of stress.
2021-01-28 | GSE144425 | GEO
Project description:The predominant outcome of cardiovascular disease (CVD) is myocardial infarction (MI), where cardiomyocytes are deprived of oxygen. To study inter-individual differences in cardiomyocytes’ response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We characterized gene expression levels, chromatin accessibility, and methylation profiles in these cardiomyocytes in four culturing conditions that correspond to normoxia (10% O2), hypoxia (1% O2) and short or long-term re-oxygenation (back to 10% O2). In our population sample, 2,113 genes change their expression following hypoxia and short- or long-term re-oxygenation. Using available genotypes from all individuals, we identified 1,573 genes with a cis eQTL in at least one of the four culturing conditions. Taking into account the incomplete power to identify eQTLs in any given condition, we also identified 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of dynamic eQTLs, which are detected only following hypoxia, have not been previously annotated as eQTLs even in much larger collections of heart tissues. We did not detect differences in DNA methylation, or chromatin accessibility as the cells transitioned between normoxia and hypoxia, but we observed a change in chromatin accessibility in 831 genomic regions upon re-oxygenation. Differentially accessible regions are enriched for features of active regulatory regions, SINE elements, and E2F4 transcription factor binding sites . Finally, we found that genes associated with dynamic eQTLs are also associated with complex traits and disease. Our data thus demonstrate how unique genetic effects on gene expression, which are likely relevant for disease, can be uncovered under conditions of stress.
2021-01-28 | GSE144424 | GEO
Project description:The predominant outcome of cardiovascular disease (CVD) is myocardial infarction (MI), where cardiomyocytes are deprived of oxygen. To study inter-individual differences in cardiomyocytes’ response to hypoxia, we established an in vitro model of induced pluripotent stem cell-derived cardiomyocytes from 15 individuals. We characterized gene expression levels, chromatin accessibility, and methylation profiles in these cardiomyocytes in four culturing conditions that correspond to normoxia (10% O2), hypoxia (1% O2) and short or long-term re-oxygenation (back to 10% O2). In our population sample, 2,113 genes change their expression following hypoxia and short- or long-term re-oxygenation. Using available genotypes from all individuals, we identified 1,573 genes with a cis eQTL in at least one of the four culturing conditions. Taking into account the incomplete power to identify eQTLs in any given condition, we also identified 367 dynamic eQTLs, which are classified as eQTLs in at least one, but not in all conditions. A subset of dynamic eQTLs, which are detected only following hypoxia, have not been previously annotated as eQTLs even in much larger collections of heart tissues. We did not detect differences in DNA methylation, or chromatin accessibility as the cells transitioned between normoxia and hypoxia, but we observed a change in chromatin accessibility in 831 genomic regions upon re-oxygenation. Differentially accessible regions are enriched for features of active regulatory regions, SINE elements, and E2F4 transcription factor binding sites . Finally, we found that genes associated with dynamic eQTLs are also associated with complex traits and disease. Our data thus demonstrate how unique genetic effects on gene expression, which are likely relevant for disease, can be uncovered under conditions of stress.
2021-01-28 | GSE144423 | GEO
Project description:DNA ligase I (LigI), the predominant enzyme that joins Okazaki fragments, interacts with PCNA and Pol d. LigI also interacts with UHRF1, linking Okazaki fragment joining with DNA maintenance methylation. Okazaki fragments can also be joined by a relatively poorly characterized DNA ligase IIIa (LigIIIa)-dependent backup pathway. Here we examined the effect of LigI-deficiency on proteins at the replication fork. Notably, LigI-deficiency did not alter the kinetics of association of the PCNA clamp, the leading strand polymerase Pol e, DNA maintenance methylation proteins and core histones with newly synthesized DNA. While the absence of major changes in replication and methylation proteins is consistent with the similar proliferation rate and DNA methylation levels of the LIG1 null cells compared with the parental cells, the increased levels of LigIIIa/XRCC1 and Pol d at the replication fork and in bulk chromatin indicate that there are subtle replication defects in the absence of LigI. Interestingly, the non-replicative histone H1 variant, H1.0, is present in the chromatin of LigI-deficient mouse and human cells. This alteration was not corrected by expression of wild type LigI, suggesting that it is a stable epigenetic change that may contribute to the immunodeficiencies linked with inherited LigI-deficiency syndrome.
2023-04-04 | PXD039547 | Pride
Project description:Studies correlating genetic variation to gene expression facilitate the interpretation of common human phenotypes and disease. As functional variants may be operating in a tissue-dependent manner, we performed gene expression profiling and association with genetic variants (SNPs) on three cell types of 85 individuals. After excluding 10 outlier individuals detected through principal component analysis, we detected cell type-specific genetic effects, with 69 - 80% of regulatory variants operating in a cell type-specific manner and identified multiple eQTLs per gene, unique or shared among cell types and positively correlated with the number of transcripts per gene. Cell type specific eQTLs were found at larger distances from genes and lower effect size similar to known enhancers. These data suggest that the complete regulatory variant repertoire can only be uncovered in the context of cell type specificity. Total RNA was extracted from fibroblasts, LCLs, and T-cells of the 85 unrelated individuals of the GenCord. Two one-quarter scale Message Amp II reactions (Ambion, Foster City, CA) were performed for each RNA extraction with 200 ng of total RNA. 1.5 μg of cRNA was hybridized to a commercial whole-genome expression array (WG-6 v3 Expression BeadChip, Illumina) to quantify transcript abundance. In total there were two technical replicates (labeling and hybridization) for each RNA sample.
2010-08-20 | E-GEOD-17080 | biostudies-arrayexpress
Project description:Steady-state expression quantitative trait loci (eQTLs) explain only a fraction of disease-associated loci identified through genome-wide association studies (GWAS), while eQTLs involved in gene-by-environment (GxE) interactions have rarely been characterized in humans due to experimental challenges. Using a baboon model, we found hundreds of eQTLs that emerge in adipose, liver, and muscle after prolonged exposure to high dietary fat and cholesterol. Diet-responsive eQTLs exhibit genomic localization and genic features that are distinct from steady-state eQTLs. Furthermore, the human orthologs associated with diet-responsive eQTLs are enriched for GWAS genes associated with human metabolic traits, suggesting that context-responsive eQTLs with more complex regulatory effects are likely to explain GWAS hits that do not seem to overlap with standard eQTLs. Our results highlight the complexity of genetic regulatory effects and the potential of eQTLs with disease-relevant GxE interactions in enhancing the understanding of GWAS signals for human complex disease using nonhuman primate models.
2023-12-27 | GSE227346 | GEO
Project description:While regulation of transcription, replication and cell division relies on dynamic protein binding to DNA and chromatin, it is unclear which regulatory components remain bound to compacted mitotic chromosomes. To comprehensively quantify the chromatin-associated proteome in different phases of the cell cycle, we utilized the buoyant density of DNA-protein complexes after crosslinking. This revealed variable associations for thousands of proteins to DNA including their frequent and variable phosphorylation. While epigenetic modifiers that promote transcription are lost from mitotic chromatin, repressive modifiers generally remain associated. Interestingly, while proteins involved in transcriptional elongation are evicted, most identified transcription factors are retained on mitotic chromatin to varying degrees, including core promoter binding proteins. This predicts conservation of the regulatory landscape on mitotic chromosomes, which genome-wide measurements of chromatin accessibility confirm. This work establishes a novel approach to study chromatin, provides a comprehensive catalogue of chromatin changes during the cell cycle, and reveals the degree with which the genomic regulatory landscape is maintained through mitosis.
2018-09-06 | PXD008033 | Pride