Adjusting methylation levels with nucleus proportions highlights functional significance of differentially methylated cytosines associated with pre-eclampsia
Year: 2024
Type: article
Study design: Observational Study
Abstract: Studies on DNA methylation alterations associated with pre-eclampsia (PE) have improved our understanding of the mechanisms underlying this disorder. However, differentially methylated cytosines (DMCs) have not been adjusted for cell-type heterogeneity, hampering the identification of alterations that drive disease risk. Using a reference-based, cell-type deconvolution approach, we estimated the nuclear proportions of 335 placental samples based on DNA methylation data. We found that the nuclei of total trophoblast lineages accounted for more than 80% of the placental samples, with a significant increase in PE placentas. The nuclear proportions of stromal and Hofbauer cells decreased in PE placentas. Our nuclear proportion estimation reflected previous histological knowledge on the changes in cell type proportions in PE placentas. We corrected 2125 DMCs associated with early-onset PE for cell-type heterogeneity by adjusting for the nuclear proportions and observed a notable reduction in the association signals, with 145 probes not reaching epigenome-wide significance. After correction, the top 200 significant DMCs were strongly enriched in active enhancers in trophoblast lineages, whereas 145 non-significant probes were enriched in regions with a quiescent state of chromatin. Our results suggest that future epigenetic studies of PE should focus on functional regulatory sequences.
Source: Molecular Human Reproduction
Authors: Xiaoguo Zheng, Yanqin Wen, Xinzhi Zhao
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: bronze
Award: G7396206057
OpenAlex ID: W4402392022