Placental and Immune Cell DNA Methylation Reference Panel for Bulk Tissue Cell Composition Estimation in Epidemiological Studies
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PROVIDER: PRJNA1132943 | ENA |
REPOSITORIES: ENA
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Project description:To distinguish DNA methylation (DNAm) from cell proportion changes in whole placental villous tissue research, we developed a robust cell type-specific DNAm reference to estimate cell composition. We collated new and existing cell type DNAm profiles quantified via Illumina EPIC or 450k microarrays. To estimate cell composition, we deconvoluted whole placental samples (n=36) with robust partial correlation based on the top 30 hyper- and hypomethylated sites identified per cell type. To test deconvolution performance, we evaluated RMSE in predicting principal components of DNAm variation in 204 external placental samples. We analyzed DNAm profiles (n=368,435 sites) from 12 cell types: cytotrophoblasts (n=18), endothelial cells (n=19), Hofbauer cells (n=26), stromal cells (n=21), syncytiotrophoblasts (n=4), six lymphocyte types (n=36), and nucleated red blood cells (n=11). Median cell composition was consistent with placental biology: 60.9% syncytiotrophoblast, 17.3% stromal, 8.8% endothelial, 3.7% cytotrophoblast, 3.7% Hofbauer, 1.7% nucleated red blood cells, and 1.2% neutrophils. Our expanded reference outperformed an existing reference in predicting DNAm variation (PC1, 15.4% variance explained, IQR=21.61) with cell composition estimates (RMSEP: 8.62 vs. 10.79, p-value<0.001). This cell type reference can robustly estimate cell composition from whole placental DNAm data to detect important cell types, reveal biological mechanisms, and improve causal inference.
2024-12-03 | GSE271697 | GEO
Project description:Background: DNA methylation (DNAm) profiling has emerged as a powerful tool for characterizing the placental methylome. However, previous studies have focused primarily on whole placental tissue, which is a mixture of epigenetically distinct cell populations. Here, we present the first methylome-wide analysis of first trimester (n=9) and term (n=19) human placental samples of four cell populations: trophoblasts, Hofbauer cells, endothelial cells, and stromal cells, using the Illumina EPIC methylation array, which quantifies DNAm at >850,000 CpGs. Results: The most distinct DNAm profiles were those of placental trophoblasts, which are central to many pregnancy-essential functions, and Hofbauer cells, which are a rare fetal-derived macrophage population. Cell-specific DNAm occurs at functionally-relevant genes, including genes associated with placental development and preeclampsia. Known placental-specific methylation marks, such as those associated with genomic imprinting, repetitive element hypomethylation, and placental partially methylated domains, were found to be more pronounced in trophoblasts and often absent in Hofbauer cells. Lastly, we characterize the cell composition and cell-specific DNAm dynamics across gestation. Conclusions: Our results provide a comprehensive analysis of DNAm in human placental cell types from first trimester and term pregnancies. This data will serve as a useful DNAm reference for future placental studies, and we provide access to this data via download from dbGAP (phs002013.v1.p1), through interactive exploration from the web browser (https://robinsonlab.shinyapps.io/Placental_Methylome_Browser/), and through the R package planet, which allows estimation of cell composition directly from placental DNAm data.
2020-10-21 | GSE159526 | GEO
Project description:Saliva is a widely used biological sample, especially in pediatric research, containing a heterogenous mixture of immune and epithelial cells. Associations of exposure or disease with saliva DNA methylation can be influenced by cell-type proportions. Here, we developed a saliva cell-type DNA methylation reference panel to estimate interindividual cell-type heterogeneity in whole saliva studies. Saliva was collected from 22 children (7-16 years) and sorted into immune and epithelial cells, using size exclusion filtration and magnetic bead sorting. DNA methylation was measured using the Illumina MethylationEPIC BeadChip. We assessed cell-type differences in DNA methylation profiles and tested for enriched biological pathways. Immune and epithelial cells differed at 181,577 (22.8%) DNA methylation sites (t-test p < 6.28 × 10-8). Immune cell hypomethylated sites are mapped to genes enriched for immune pathways (p < 3.2 × 10-5). Epithelial cell hypomethylated sites were enriched for cornification (p = 5.2 × 10-4), a key process for hard palette formation. Saliva immune and epithelial cells have distinct DNA methylation profiles which can drive whole-saliva DNA methylation measures. A primary saliva DNA methylation reference panel, easily implemented with an R package, will allow estimates of cell proportions from whole saliva samples and improve epigenetic epidemiology studies by accounting for measurement heterogeneity by cell-type proportions.
| S-EPMC8865319 | biostudies-literature
Project description:Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant. Human TCE exposure is prevalent, though epidemiological studies testing TCE exposure and adverse birth outcomes are inconclusive. The TCE metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) exhibits toxicity at human-relevant concentrations in a placental cell line. To date, DCVC cytotoxicity mechanistic studies have been limited to single molecular signaling pathways and biological responses. In the current study, genome-wide gene expression and gene set enrichment analyses (GSEA) were used to identify novel genes and pathways altered by human exposure-relevant DCVC concentrations in the human placental cell line HTR-8/SVneo. The results of this study were compared to a parallel study using placental villous exlant tissues.
2021-03-16 | GSE154339 | GEO
Project description:The placenta is a central organ during early development, influencing trajectories of health and disease. DNA methylation (DNAm) studies of human placenta improve our understanding of how its function relates to disease risk. However, DNAm studies can be biased by cell type heterogeneity, so it is essential to control for this in order to reduce confounding and increase precision. Computational cell type deconvolution approaches have proven to be very useful for this purpose. For human placenta, however, an assessment of the performance of these estimation methods is still lacking. Here, we examine the performance of a newly available reference-based cell type estimation approach and compare it to an often-used reference-free cell type estimation approach, namely RefFreeEWAS, in placental genome-wide DNAm samples taken at birth and from chorionic villus biopsies early in pregnancy using three independent studies comprising over 1000 samples. We found both reference-free and reference-based estimated cell type proportions to have predictive value for DNAm, however, reference-based cell type estimation outperformed reference-free estimation for the majority of data sets. Reference-based cell type estimations mirror previous histological knowledge on changes in cell type proportions through gestation. Further, CpGs whose variation in DNAm was largely explained by reference-based estimated cell type proportions were in the proximity of genes that are highly tissue-specific for placenta. This was not the case for reference-free estimated cell type proportions. We provide a list of these CpGs as a resource to help researchers to interpret results of existing studies and improve future DNAm studies of human placenta.
| S-EPMC8813756 | biostudies-literature
Project description:EPIDEMIOLOGICAL TYPING OF SERRATIA MARCESCENS
| PRJEB28358 | ENA
Project description:Trichloroethylene (TCE) is an industrial solvent and widespread environmental contaminant. Human TCE exposure is prevalent, though epidemiological studies testing TCE exposure and adverse birth outcomes are inconclusive. The TCE metabolite S-(1,2-dichlorovinyl)-L-cysteine (DCVC) exhibits toxicity at human-relevant concentrations in a placental cell line. To date, DCVC cytotoxicity mechanistic studies have been limited to single molecular signaling pathways and biological responses. In the current study, genome-wide gene expression and gene set enrichment analyses (GSEA) were used to identify novel genes and pathways altered by human exposure-relevant DCVC concentrations in human placental villous explant tissues. The results of this study were compared to a parallel study using the placental cell line HTR-8/SVneo.
2021-03-16 | GSE154489 | GEO