Samantha L. Wilson

Number of Children and Telomere Length in Women: A Prospective, Longitudinal Evaluation.

Life history theory (LHT) predicts a trade-off between reproductive effort and the pace of biological aging. Energy invested in reproduction is not available for tissue maintenance, thus having more offspring is expected to lead to accelerated senescence. Studies conducted in a variety of non-human species are consistent with this LHT prediction. Here we investigate the relationship between the number of surviving children born to a woman and telomere length (TL, a marker of cellular aging) over 13 years in a group of 75 Kaqchikel Mayan women. Contrary to LHT’s prediction, women who had fewer children exhibited shorter TLs than those who had more children (p = 0.045) after controlling for TL at the onset of the 13-year study period. An “ultimate” explanation for this apparently protective effect of having more children may lay with human’s cooperative-breeding strategy. In a number of socio-economic and cultural contexts, having more chilren appears to be linked to an increase in social support for mothers (e.g., allomaternal care). Higher social support, has been argued to reduce the costs of further reproduction. Lower reproductive costs may make more metabolic energy available for tissue maintenance, resulting in a slower pace of cellular aging. At a “proximate” level, mechanisms involved may include the actions of the gonadal steroid estradiol, which increases dramatically during pregnancy. Estradiol is known to protect TL from the effects of oxidative stress as well as increase telomerase activity, an enzyme that maintains TL. Future research should explore the potential role of social support as well as that of estradiol and other potential biological pathways in the trade-offs between reproductive effort and the pace of cellular aging within and among human as well as in non-human populations.

Placental DNA methylation at term reflects maternal serum levels of INHA and FN1, but not PAPPA, early in pregnancy

BackgroundEarly detection of pregnancies at risk of complications, such as intrauterine growth restriction (IUGR) and preeclampsia (PE), is critical for improved monitoring and preventative treatment to optimize health outcomes. We predict that levels of placental-derived proteins circulating in maternal blood reflect placental gene expression, which is associated with placental DNA methylation (DNAm) profiles. As such, placental DNAm profiling may be useful to distinguish pregnancies at risk of developing complications and correlation between DNAm and protein levels in maternal blood may give further evidence for a protein’s use as a biomarker. However, few studies investigate all clinical parameters that may influence DNAm and/or protein expression, which can significantly affect the relationship between these measures.Results Candidate genes were chosen based on i) reported alterations of protein levels in maternal blood and ii) observed changes in placental DNAm (∆β > 0.05 and False Discovery Rate (FDR) <0.05) in pregnancies complicated by PE/IUGR. Fibronectin (FN1) enhancer DNAm and placental gene expression were inversely correlated (r = −0.88 p < 0.01). The same trend was observed between promoter DNAm and gene expression for INHBA and PAPPA, though not significant. INHBA and FN1 DNAm was associated with gestational–age corrected birth weight, while INHA levels were associated with fetal: placental weight ratio and FN1 level was associated with maternal body mass index (BMI).DNAm at the INHBA promoter in the term placenta was negatively correlated with second trimester maternal serum levels (r = −0.50 p = 0.01) and DNAm at the FN1 enhancer was negatively associated with third trimester maternal serum levels (r = −0.38, p = 0.009). However, a similar correlation was not found for PAPPA.ConclusionsThese results show that establishing a correlation between altered DNAm in the term placenta and altered maternal serum levels of the corresponding protein, is affected by a number of factors. Nonetheless, the correlation between placental DNAm of INHBA/FN1 and maternal serum INHA/FN1 levels indicate that DNAm may be a useful tool to identify novel biomarkers for adverse pregnancy outcomes in some cases.

Noninvasive nucleic acid–based approaches to monitor placental health and predict pregnancy-related complications

During pregnancy, the placenta releases a variety of nucleic acids (including deoxyribonucleic acid, messenger ribonucleic acid, or microribonucleic acids) either as a result of cell turnover or as an active messaging system between the placenta and cells in the maternal body. The profile of released nucleic acids changes with the gestational age and has been associated with maternal and fetal parameters. It also can directly reflect pathological changes in the placenta. Nucleic acids may therefore provide a rich source of novel biomarkers for the prediction of pregnancy complications. However, their utility in the clinical setting depends, first, on overcoming some technical considerations in their quantification, and, second, on developing a better understanding of the factors that influence their function and abundance.

Mining DNA methylation alterations towards a classification of placental pathologies

Abstract Placental health is a key component to a successful pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE). However, the relationship between these disorders remains unclear. While DNA methylation (DNAm) alterations have been identified in PE and IUGR, these entities can overlap and few studies have analysed them separately. This study aims to utilize DNAm profiling to better understand the underlying placental variation associated with PE and IUGR. Placental samples from a discovery (43 controls, 22 EOPE, 18 LOPE, 11 IUGR) and validation cohort (15 controls, 22 EOPE, 11 LOPE) were evaluated using the Illumina HumanMethylation450 array. To account for gestational age (GA) effects, EOPE samples were compared with pre-term births of varying etiologies (GA <37 weeks). LOPE and IUGR were compared with term controls (GA >37 weeks). While 1703 sites were differentially methylated (DM) (FDR < 0.05, Δβ > 0.1) in EOPE, few changes were associated with LOPE (N = 5), or IUGR (N = 0). Of the 1703 EOPE sites, 599 validated in the second cohort. Using these 599 sites, both cohorts clustered into three distinct groups. Interestingly, LOPE samples diagnosed between 34 and 36 weeks with co-occurring IUGR clustered with the EOPE. DNAm profiling may provide an independent tool to refine clinical/pathological diagnoses into subgroups with more uniform pathology. Despite large changes observed in EOPE, there were challenges in reproducing genome-wide DNAm hits that are discussed.

Placental telomere length decline with gestational age differs by sex and TERT, DNMT1, and DNMT3A DNA methylation

INTRODUCTION Telomere length (TL) has been suggested to be influenced by inherited genetic and epigenetic variation, hormonal effects, oxidative stress and age. However, the dynamics of TL during in utero development have not been well explored. This study investigates the relationship between placental TL and sex, gestational age (GA), and DNA methylation (DNAm). Placental TL is further evaluated in pregnancies complicated by preeclampsia (PE) and intrauterine growth restriction (IUGR), conditions hypothesized to lead to decreased placental TL due to increased oxidative stress. METHODS Average TL in 21 early-onset PE (EOPE), 18 late-onset PE (LOPE), 9 IUGR, 59 viable and 33 non-viable control placentas were measured by qPCR. Of these, 13 control, 20 EOPE, 17 LOPE, and 8 IUGR samples were also run on the Illumina 450K array. ANOVA was used to compare TL between controls and EOPE, LOPE, and IUGR. Linear regression correcting for GA and sex, assessed the association between TL and DNAm in biologically-relevant genes (TERC, TERT, DNMT1, DNMT3a, DNMT3b), and array-wide. RESULTS Male sex and increasing GA were associated with shorter placental TL. Correcting for these factors, no significant difference in TL was observed between EOPE, LOPE, and IUGR placentas compared to controls. Targeted analysis revealed TL was associated with DNAm at TERT, DNMT1, and DNMT3a. An array-wide approach found no additional sites associated with TL. CONCLUSION Variability in placental TL is associated with alterations in DNAm at TERT, DNMT1, and DNMT3a. Placental TL is not strongly influenced by EOPE, LOPE, or IUGR.

Review: placental biomarkers for assessing fetal health

The placenta is a multifunctional organ that regulates key aspects of pregnancy maintenance and fetal development. As the placenta is in direct contact with maternal blood, cellular products (DNA, RNA, proteins, etc.) from the placenta can enter maternal circulation by a variety of ways. The application of serum proteins and circulating placental derived DNA has been well demonstrated for the diagnosis of aneuploidy, and there is great interest in exploring the use of placental biomarkers for the prediction of a range of fetal health parameters. In this review, we discuss how placental biomarkers might be used for the diagnosis and early detection of preeclampsia, fetal growth restriction and inflammation associated with preterm birth. We emphasize how increased understanding of the underlying placental biology can aid in the interpretation of such approaches and development of new biomarkers that can help predict the onset of pregnancy and neonatal health concerns before they manifest.

IFPA meeting 2016 workshop report I: genomic communication, bioinformatics, trophoblast biology and transport systems

Workshops are an important part of the IFPA annual meeting as they allow for discussion of specialized topics. At IFPA meeting 2016 there were twelve themed workshops, four of which are summarized in this report. These workshops covered innovative technologies applied to new and traditional areas of placental research: 1) genomic communication; 2) bioinformatics; 3) trophoblast biology and pathology; 4) placental transport systems.

Epigenetic Modifications in the Human Placenta

Abstract Epigenetic changes regulate developmental processes such as cell differentiation, X-chromosome inactivation and genomic imprinting. They also play an important role in modulating gene expression up or down in response to external (e.g., environmental) influences. Epigenetic processes in the placenta are quite distinct from other tissues, reflecting its unusual development and role as the interface between the mother and fetus. Investigation of the placental epigenome can add insight into (i) the unique aspects of placental development, including its relationship to metastatic processes in cancer; (ii) pathogenesis related to placental mediated pregnancy disorders; (iii) how in utero exposures, such as maternal nutrition, stress, drug use, and metabolic disease, can affect fetal health and long-term developmental outcomes; and (iv) possible utility in prenatal diagnosis.

Epigenetic regulation of placental gene expression in transcriptional subtypes of preeclampsia

BackgroundPreeclampsia (PE) is a heterogeneous, hypertensive disorder of pregnancy, with no robust biomarkers or effective treatments. We hypothesized that this heterogeneity is due to the existence of multiple subtypes of PE and, in support of this hypothesis, we recently identified five clusters of placentas within a large gene expression microarray dataset (N = 330), of which four (clusters 1, 2, 3, and 5) contained a substantial number of PE samples. However, while transcriptional analysis of placentas can subtype patients, we propose that the addition of epigenetic information could discern gene regulatory mechanisms behind the distinct PE pathologies, as well as identify clinically useful potential biomarkers.ResultsWe subjected 48 of our samples from transcriptional clusters 1, 2, 3, and 5 to Infinium HumanMethylation450 arrays. Samples belonging to transcriptional clusters 1–3 still showed visible relationships to each other by methylation, but cluster 5, with known chromosomal abnormalities, no longer formed a cohesive group. Within transcriptional clusters 2 and 3, controlling for fetal sex and gestational age in the identification of differentially methylated sites, compared to the healthier cluster 1, dramatically reduced the number of significant sites, but increased the percentage that demonstrated a strong linear correlation with gene expression (from 5% and 2% to 9% and 8%, respectively). Locations exhibiting a positive relationship between methylation and gene expression were most frequently found in CpG open sea enhancer regions within the gene body, while those with a significant negative correlation were often annotated to the promoter in a CpG shore region. Integrated transcriptome and epigenome analysis revealed modifications in TGF-beta signaling, cell adhesion, oxidative phosphorylation, and metabolism pathways in cluster 2 placentas, and aberrations in antigen presentation, allograft rejection, and cytokine-cytokine receptor interaction in cluster 3 samples.ConclusionsOverall, we have established DNA methylation alterations underlying a portion of the transcriptional development of “canonical” PE in cluster 2 and “immunological” PE in cluster 3. However, a significant number of the observed methylation changes were not associated with corresponding changes in gene expression, and vice versa, indicating that alternate methods of gene regulation will need to be explored to fully comprehend these PE subtypes.

The value of DNA methylation profiling in characterizing preeclampsia and intrauterine growth restriction

Placental health is a key component to healthy pregnancy. Placental insufficiency (PI), inadequate nutrient delivery to the fetus, is associated with preeclampsia (PE), a maternal hypertensive disorder, and intrauterine growth restriction (IUGR), pathologically poor fetal growth. PI is more common in early-onset PE (EOPE) than late-onset PE (LOPE). However, the relationship between these disorders remains unclear. While DNA methylation (DNAm) alterations have been identified in PE and IUGR, these entities can overlap and few studies have analyzed these separately. This study aims to identify altered DNAm in EOPE, LOPE, and normotensive IUGR, validate these alterations, and use them to better understand the relationships between these related disorders. Placental samples from a discovery cohort (43 controls, 22 EOPE, 18 LOPE, 11 IUGR) and validation cohort (15 controls, 22 EOPE, 11 LOPE) were evaluated using the Illumina HumanMethylation450 array. To minimize gestational age (GA) effects, EOPE samples were compared to pre-term controls (GA <37 weeks), while LOPE and IUGR were compared to term controls (GA >37 weeks). There were 1703 differentially methylated (DM) sites (FDR<0.05, Δβ>0.1) in EOPE, 5 in LOPE, and 0 in IUGR. Of the 1703 EOPE sites, 599 were validated in the second cohort. These sites cluster samples from both cohorts into 3 distinct methylation clusters. Interestingly, LOPE samples diagnosed between 34-36 weeks with co-occurring IUGR clustered with the EOPE methylation cluster. DNAm profiling may provide an independent tool to refine clinical diagnoses into subgroups with more uniform pathology. The challenges in reproducing genome-wide DNAm studies are also discussed.