SExual Epigenetic Dimorphism in The Human Placenta: Implications for Susceptibility During The Prenatal Period

Martin, Elizabeth M.; Smeester, Lisa; Bommarito, Paige A.; Grace, Matthew R.; Boggess, Kim; Kuban, Karl; Karagas, Margaret R.; Marsit, Carmen J.; O’Shea, T. Michael; Fry, Rebecca C.

doi:10.2217/epi-2016-0132

Cited by 99 publications

(91 citation statements)

References 59 publications

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“…Since both clusters 2 and 3 are significantly younger than cluster 1 ( p < 0.01 and p = 0.02, respectively), this fits with the knowledge that placentas become progressively more methylated with time [ 36 ], while in cluster 3, a moderate bias in fetal sex ( p = 0.12) may have also been involved. Additionally, controlling for fetal sex and GA substantially increased the proportion of significant sites that showed a strong linear relationship with gene expression (5% to 9% in cluster 2; 2% to 8% in cluster 3), thereby confirming that a large number of sites in the genome undergo DNA methylation changes in response to differences in these two factors that are independent of epigenetic regulation and gene expression [ 9 , 36 , 37 ].…”

Section: Discussionmentioning

confidence: 98%

Epigenetic regulation of placental gene expression in transcriptional subtypes of preeclampsia

et al. 2018

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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.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0463-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 98%

Epigenetic regulation of placental gene expression in transcriptional subtypes of preeclampsia

et al. 2018

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“…The most extensively profiled sexually dimorphic epigenetic mark is DNA methylation. Sex-specific methylation patterns have been observed in blood [74][75][76][77], placenta [78], liver [79][80][81][82], pancreas [83], muscle [84], heart [81], and brain [81,[85][86][87][88][89]. Sex differences in histone modifications have also been described, although thus far only in mouse brain [90,91].…”

Section: Sex Differences In Epigeneticsmentioning

confidence: 99%

Sex differences in cancer mechanisms

et al. 2020

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We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab-and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.

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“…Effects of prenatal exposure to endocrine disruptors & toxic metals on the fetal epigenome Review mental differences between placentas derived from male or female fetuses may result in sexually dimorphic responses to environmental exposures [132]. It has recently been shown that gene-specific methylation differs between male and female placentas and these genes are enriched for immune function, transport of substances across the placenta, and transcription factors [133]. Further substantiating these findings, femaleand male-derived placentas have differential expression levels of immune-related genes.…”

Section: Review Bommarito Martin and Frymentioning

confidence: 99%

Effects of Prenatal Exposure to Endocrine Disruptors and Toxic Metals on The Fetal Epigenome

2017

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Exposure to environmental contaminants during pregnancy has been linked to adverse outcomes at birth and later in life. The link between prenatal exposures and latent health outcomes suggests that these exposures may result in long-term epigenetic reprogramming. Toxic metals and endocrine disruptors are two major classes of contaminants that are ubiquitously present in the environment and represent threats to human health. In this review, we present evidence that prenatal exposures to these contaminants result in fetal epigenomic changes, including altered global DNA methylation, gene-specific CpG methylation and microRNA expression. Importantly, these changes may have functional cellular consequences, impacting health outcomes later in life. Therefore, these epigenetic changes represent a critical mechanism that warrants further study.

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SExual Epigenetic Dimorphism in The Human Placenta: Implications for Susceptibility During The Prenatal Period

Cited by 99 publications

References 59 publications

Epigenetic regulation of placental gene expression in transcriptional subtypes of preeclampsia

Epigenetic regulation of placental gene expression in transcriptional subtypes of preeclampsia

Sex differences in cancer mechanisms

Effects of Prenatal Exposure to Endocrine Disruptors and Toxic Metals on The Fetal Epigenome

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