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Infertility and treatments utilized have minimal effects on first trimester human placenta DNA methylation and gene expression.

ABSTRACT: OBJECTIVE: To determine whether deoxyribonucleic acid (DNA) methylation alterations exist in the first trimester human placenta between conceptions using fertility treatments and those that do not and, if so, whether differences are the result of underlying infertility or fertility treatments. We also assessed whether significant alterations led to changes in gene expression using bulk total RNA-seq from the same cohort (see Lee et al 2019, PMID: 30611556, NCBI GEO GSE215421). DESIGN: We compared DNA methylation of the first trimester placenta from singleton pregnancies that resulted in live births from unassisted, in vitro fertilization (IVF), and non-IVF fertility treatment (NIFT) conceptions using the Infinium MethylationEPIC BeadChip array. Differentially methylated probes (DMPs) were identified using a generalized linear model adjusted for fetal sex. Associated genes for significant CpG sites were cross-references in RNA-seq results to determine whether methylation alterations lead to differences in gene expression. SETTING: Academic medical center. PATIENTS: A total of 138 singleton pregnancies undergoing chorionic villus sampling resulting in a live birth were recruited for methylation analysis (56 unassisted, 38 NIFT, and 44 IVF conceptions). INTERVENTIONS AND TREATMENTS: In vitro fertilization-conceived pregnancy or pregnancy conceived via NIFT, such as ovulation induction and intrauterine insemination. RESULTS: Of the 741,145 CpG probes analyzed in the placenta, few were significant at Bonferroni <0.05: 185 CpG sites (0.025%) significant in pregnancies conceived with the fertility treatments (NIFT + IVF) versus unassisted conceptions; 28 in NIFT versus unassisted; 195 in IVF versus unassisted; and only 13 (0.0018%) in IVF versus NIFT conceptions. CONCLUSION: Underlying infertility is the most significant contributor to the minimal differences in first trimester placental methylation, and not the specific fertility treatment used, such as IVF.

ORGANISM(S): Homo sapiens

PROVIDER: GSE289196 | GEO | 2025/02/11

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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Infertility and treatments utilized have minimal effects on first trimester human placenta DNA methylation and gene expression.

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