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Evidence for widespread changes in promoter methylation profile in human placenta in response to increasing gestational age and environmental/stochastic factors.

ABSTRACT: Background: the human placenta facilitates the exchange of nutrients, gas and waste between the fetal and maternal circulations. It also protects the fetus from the maternal immune response. Due to its role at the feto-maternal interface, the placenta is subject to many environmental exposures that can potentially alter its epigenetic profile. Previous studies have reported gene expression differences in placenta over gestation, as well as inter-individual variation in expression of some genes. However, the factors contributing to this variation in gene expression remain poorly understood. Results: in this study, we performed a genome-wide DNA methylation analysis of gene promoters in placenta tissue from three pregnancy trimesters. We identified large-scale differences in global DNA methylation levels between first, second and third trimesters, with an overall progressive increase in average methylation from first to third trimester. The most differentially methylated genes included many immune regulators, reflecting the change in placental immuno-modulation as pregnancy progresses. We also detected increased inter-individual variation in the third trimester relative to first and second, supporting an accumulation of environmentally induced (or stochastic) changes in DNA methylation pattern. These highly variable genes were enriched for those involved in amino acid and other metabolic pathways, potentially reflecting the adaptation of the human placenta to different environments. Conclusions : the identification of cellular pathways subject to drift in response to environmental influences provide a basis for future studies examining the role of specific environmental factors on DNA methylation pattern and placenta-associated adverse pregnancy outcomes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE31781 | GEO | 2011/09/01

SECONDARY ACCESSION(S): PRJNA145291

REPOSITORIES: GEO

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Project description:Human placenta bulk mRNA-sequencing from n=124 first trimester (59 female, 65 male) and n=43 third trimester (18 female, 25 male) tissue samples. A subset of 23 pregnancies has matched placenta tissue collected at both first and third trimester. Tissue was collected at Cedars-Sinai Medical Center in Los Angeles, California, USA. First trimester placenta was collected at gestational ages of 70-100 days from leftover tissue from chorionic villus sampling for prenatal genetic diagnosis, after cleaning to remove maternal decidua. Third trimester placenta was collected after delivery at gestational ages 254-290 days from the fetal side near the umbilical cord insertion site beneath the amnion. Tissue was stored in RNAlater RNA Stabilization Solution (Invitrogen) at -80C until further processing. All pregnancies were conceived without fertility treatments, were normal karyotype, and resulted in live singleton births. Mothers with pre-existing diabetes or hypertension were excluded from the study, but not excluded if complications developed during pregnancy, though most pregnancies were uncomplicated. The average parental age was advanced (over 35 years old) but principal components analysis did not show clustering by either maternal or paternal age. RNA extraction was performed with physical homogenization of tissue followed by the AllPrep DNA/RNA/miRNA Universal Kit (QIAGEN), then 1 ug of the total RNA elution was used for library construction using the Illumina TruSeq Stranded mRNA library preparation kit (Illumina), with polyA mRNA selection then cDNA synthesis using SuperScript II reverse transcriptase (Invitrogen) and random primers. The cDNA was converted into double stranded DNA and PCR-amplified, then purified with Agencourt AMPure XP beads (Beckman Coulter). Sample libraries were multiplexed and sequenced on a NovaSeq 6000 platform (Illumina) using 75bp single-end mRNA-sequencing, with average 30 million reads per sample. Differential expression analysis was performed with DEseq2 to compare first versus third trimester placenta, adjusted for fetal sex [PubMed ID: 38271627]. Subanalyses were also performed to identify sex differences.

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Evidence for widespread changes in promoter methylation profile in human placenta in response to increasing gestational age and environmental/stochastic factors.

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