Kyle A Campbell, Justin A Colacino, John Dou, Dana C Dolinoy, Sung Kyun Park, Rita Loch-Caruso, Vasantha Padmanabhan, Kelly M Bakulski
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引用次数: 0
Abstract
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 root mean square error 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 (mean square error of prediction: 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.
期刊介绍:
Epigenetics publishes peer-reviewed original research and review articles that provide an unprecedented forum where epigenetic mechanisms and their role in diverse biological processes can be revealed, shared, and discussed.
Epigenetics research studies heritable changes in gene expression caused by mechanisms others than the modification of the DNA sequence. Epigenetics therefore plays critical roles in a variety of biological systems, diseases, and disciplines. Topics of interest include (but are not limited to):
DNA methylation
Nucleosome positioning and modification
Gene silencing
Imprinting
Nuclear reprogramming
Chromatin remodeling
Non-coding RNA
Non-histone chromosomal elements
Dosage compensation
Nuclear organization
Epigenetic therapy and diagnostics
Nutrition and environmental epigenetics
Cancer epigenetics
Neuroepigenetics