High‐resolution analysis of the human placental DNA methylome in early gestation

Abstract

Background/Objective We communicate high‐read‐depth bisulfite sequencing analysis of the chorionic villus (CV) DNA methylome from samples obtained between 11 and 13 weeks gestation and samples of gestationally age‐matched maternal blood cells (MBC). Methods This was achieved through solution‐phase targeted region capture (84 Mb) of bisulfite converted human DNA. Results We identified biphasic distribution of methylation in CV and MBC genomes. We found greater numbers of intermediate methylated sites (20%‐80% methylated) in CV and greater number of high methylation sites in MBC and investigated distributions of these in promoters, introns, exons, CpG islands, CpG islands shores, and enhancers. We identified differentially methylated sites distinguishing CV and MBC. These are less likely to occur in CpG islands (CGIs), particularly those that exist outside promoters, exons, and introns. We found that gene promoter and gene body methylation patterns are associated with mRNA transcriptional profiles in CV. Despite the relative hypomethylation of CV genomes, we found that these contain DM regions that are more likely to be hypermethylated in CV relative to MBC. Conclusions Our data provide novel insight into the structure and organization of the CV epigenome, which may inform future studies of placental biology and noninvasive prenatal phenotyping.

High‐resolution epigenomic liquid biopsy for noninvasive phenotyping in pregnancy

“…These results further demonstrate that the genomic location of CpG sites influences the maternal plasma methylome in early gestation. The fact that these gene regulatory element–containing regions are less likely to be hypomethylated in the plasma of pregnant women than structural genomic elements (exons/introns) is consistent with previous epigenomic analyses of early‐gestational CV samples and age‐matched maternal leukocytes (MBC) in which it was shown that although the CV genome is generally hypomethylated relative to MBC, it contains regions that cluster within CGIs, CGI shores, and enhancers that are relatively more methylated 35 …”

“…Given the apparent influence of the CV methylome on cfDNA methylation patterns in maternal plasma, we sought to determine whether specific loci that are known to have distinct epigenetic signatures in the CV genome may influence maternal plasma DNA methylation profiles in a predictable fashion. Such loci were identified from a previously published 35 comparison of CpG methylation between early‐gestational CV tissue samples (11‐13 weeks) and gestational age–matched MBCs 35 . These assays were performed using solution‐phase hybridization followed by bisulfite DNA sequencing.…”

“…MBCs 35. These assays were performed using solutionphase hybridization followed by bisulfite DNA sequencing.…”