Comparison of Genome-Wide and Gene-Specific DNA Methylation Profiling in First-Trimester Chorionic Villi From Pregnancies Conceived With Infertility Treatments

Xu, Ning; Cui, Jinrui; Wang, Erica T.; Lee, Bora; Akhlaghpour, Marzieh; Kroener, Lindsay; Williams, John; Rotter, Jerome I.; Chen, Yii‐Der I.; Goodarzi, Mark O.; Pisarska, Margareta D.

doi:10.1177/1933719116675056

Cited by 33 publications

(28 citation statements)

References 58 publications

(63 reference statements)

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“…(45, 46) As newer studies are identifying methylation differences in the placenta at term to the infertility treatment utilized as well as the potential underlying infertility earlier in gestation, future studies are necessary to determine the underlying etiology for placentation defects, whether it is the underlying infertility, the treatments utilized or the patient population. (35, 47)…”

Section: Discussionmentioning

confidence: 99%

Mode of conception does not appear to affect placental volume in the first trimester

Churchill

Wang

Goldstein

et al. 2017

Fertility and Sterility

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Objective To study whether infertility treatments, including IVF and non-IVF fertility treatments (NIFT), are associated with diseases of placental insufficiency in early gestation. First trimester placental volumes by ultrasound and chorionic villi weight during sampling (CVS) were performed to detect differences between pregnancies conceived spontaneously versus with fertility treatments. Design Retrospective cohort Setting Academic tertiary center Patients Women with singleton pregnancies undergoing CVS and first trimester ultrasound from 4–2007 to 11–2015. Interventions Estimated placental volume (EPV) was calculated from ultrasound images using a validated computation and CVS estimated tissue weight was performed using a validated visual analog scale. Main Outcomes Measured Adjusted linear regression was used to compare EPV and CVS weight based on mode of conception. Results 1977 spontaneous, 334 conceived with fertility treatments (133 NIFT, and 201 IVF) were included. Significant differences in maternal age, gravidity, hypertension and smoking status were identified. EPV and CVS weight were correlated with maternal age, gestational age, and maternal hypertension. Adjusted linear regression showed no difference in EPV in pregnancies conceived with fertility treatments versus spontaneously. CVS weight was significantly lower in the IVF conceptions in unadjusted univariate analyses. However, following adjusted regression, this was no longer significant. Conclusions Mode of conception does not appear to affect first trimester placental size. As differences in maternal age, hypertension and smoking status differ among the groups and are correlated to placental size, it may be the underlying patient population leading to abnormal placentation and insufficiency, not the fertility treatments utilized.

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Section: Discussionmentioning

confidence: 99%

Mode of conception does not appear to affect placental volume in the first trimester

Churchill

Wang

Goldstein

et al. 2017

Fertility and Sterility

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“…As previously described, collection of CVS was performed between 11 and 13 wk gestation at the Cedars-Sinai Prenatal Diagnostic Center by the same physician [22]. Leftover tissue not used for clinical genetic testing was collected under an institution review board-approved protocol at our institution.…”

Section: Methodsmentioning

confidence: 99%

“…First, methylation data from CVS-derived DNA was obtained using the Infinium HumanMethylation450 BeadChip Array (Illumina). Differential methylation patterns were seen in several genes, including at multiple CpG sites in three genes ( ANAPC2, CXCL14, and RIMS1) when comparing samples of CVS from IVF and NIFT patients [22]. IPA was then used to visualize the network of transcriptional regulators of this gene network to explain how regulators interact with one another.…”

Section: Methodsmentioning

confidence: 99%

“…In our prior study, in an attempt to control for underlying infertility, we compared genomewide DNA methylation from chorionic villus samples (CVS) from matched singleton pregnancies conceived using either fresh IVF or NIFT to determine if IVF induces epigenetic changes in the placenta during early fetal development [22]. We found similar global methylation among the groups.…”

Section: Introductionmentioning

confidence: 99%

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Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation

Lee

Kroener

et al. 2016

Biology of Reproduction

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Pregnancies resulting from fresh in vitro fertilization (IVF) cycles exposed to supraphysiologic estrogen levels have been associated with higher rates of low birth weight and small for gestational age babies. We identified GATA3, a transcription factor selectively expressed in the trophectoderm during the blastocyst stage of embryo development, in an upstream analysis of genes that were differentially methylated in chorionic villus samples between IVF and non-IVF infertility treatment pregnancies. In this study, we investigate the hypothesis that GATA3 is hormonally regulated and plays an important functional role in trophoblast migration, invasion, and placentation. We found that GATA3 expression was hormonally regulated by estradiol in HTR8/SVneo first trimester trophoblast cells; however, no change in expression was seen with progesterone treatment. Furthermore, GATA3 knockdown resulted in decreased HTR8/SVneo cell migration and invasion compared with controls. RNA sequencing of GATA3 knockdown cells demonstrated 96 differentially regulated genes compared with controls. Genes known to play an important role in cell-cell and cell-extracellular matrix interactions, cell invasion, and placentation were identified, including CTGF, CYR61, ADAMTS12, and TIMP3. Our results demonstrate estradiol down-regulates GATA3, and decreased GATA3 expression leads to impaired trophoblast cell migration and invasion, likely through regulation of downstream genes important in placentation. These results are consistent with clinical data suggesting that supraphysiologic estrogen levels seen in IVF pregnancies may play an important role in attenuated trophoblast migration, invasion, and impaired placentation. GATA3 appears to be an important regulator of placentation and may play a role in impaired outcomes associated with fresh IVF cycles.

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“…Plate and batch effects were assessed visually by principal component analysis (PCA), and data were normalized using the Chip Analysis Methylation Pipeline (ChAMP) package (implemented in R). Significantly differentially methylated loci were then analyzed using Ingenuity Pathway Analysis (IPA) and identified a number of genes to be differentially methylated …”

Section: Resultsmentioning

confidence: 81%

Optimization of techniques for multiple platform testing in small, precious samples such as human chorionic villus sampling

et al. 2016

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Background Multiple testing to understand global changes in gene expression based on genetic and epigenetic modifications is evolving. Chorionic villi, obtained for prenatal testing, is limited, but can be used to understand ongoing human pregnancies. However, optimal storage, processing and utilization of CVS for multiple platform testing has not been established. Results Leftover CVS samples were flash-frozen or preserved in RNAlater. Modifications to standard isolation kits were performed to isolate quality DNA and RNA from samples as small as 2–5 mg. RNAlater samples had significantly higher RNA yields and quality and were successfully used in microarray and RNA-sequencing (RNA-seq). RNA-seq libraries generated using 200 vs. 800 ng RNA showed similar biological coefficients of variation. RNAlater samples had lower DNA yields and quality, which improved by heating the elution buffer to 70°C. Purification of DNA was not necessary for bisulfite-conversion and genome-wide methylation profiling. CVS cells were propagated and continue to express genes found in freshly-isolated chorionic villi. Conclusions CVS samples preserved in RNAlater are superior. Our optimized techniques provide specimens for genetic, epigenetic and gene expression studies from a single small sample which can be used to develop diagnostics and treatments using a systems biology approach in the prenatal period.

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Comparison of Genome-Wide and Gene-Specific DNA Methylation Profiling in First-Trimester Chorionic Villi From Pregnancies Conceived With Infertility Treatments

Cited by 33 publications

References 58 publications

Mode of conception does not appear to affect placental volume in the first trimester

Mode of conception does not appear to affect placental volume in the first trimester

Function and Hormonal Regulation of GATA3 in Human First Trimester Placentation

Optimization of techniques for multiple platform testing in small, precious samples such as human chorionic villus sampling

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