Associations between imprinted gene expression in the placenta, human fetal growth and preeclampsia

Genomic imprinting is essential for normal placental and fetal growth. One theory to explain the evolution of imprinting is the kinship theory (KT), which predicts that genes that are paternally expressed will promote fetal growth, whereas maternally expressed genes will suppress growth. We investigated the expression of imprinted genes using microarray measurements of expression in term placentae. Correlations between birthweight and the expression levels of imprinted genes were more significant than for non-imprinted genes, but did not tend to be positive for paternally expressed genes and negative for maternally expressed genes. Imprinted genes were more dysregulated in preeclampsia (a disorder associated with placental insufficiency) than randomly selected genes, and we observed an excess of patterns of dysregulation in preeclampsia that would be expected to reduce nutrient allocation to the fetus, given the predictions of the KT. However, we found no evidence of coordinated regulation among these imprinted genes. A few imprinted genes have previously been shown to be associated with fetal growth and preeclampsia, and our results indicate that this is true for a broader set of imprinted genes.

Download Full-text

Differences in Placental Imprinted Gene Expression across Preeclamptic and Non-Preeclamptic Pregnancies

Genes ◽

10.3390/genes11101146 ◽

2020 ◽

Vol 11 (10) ◽

pp. 1146

Author(s):

Maya A. Deyssenroth ◽

Qian Li ◽

Carlos Escudero ◽

Leslie Myatt ◽

Jia Chen ◽

...

Keyword(s):

Gene Expression ◽

Fetal Growth ◽

Pregnancy Complications ◽

Fetal Growth Restriction ◽

Late Onset ◽

Critical Role ◽

Growth Restriction ◽

Imprinted Genes ◽

Imprinted Gene ◽

Expression Levels

Preeclampsia is a multi-systemic syndrome that presents in approximately 5% of pregnancies worldwide and is associated with a range of subsequent postpartum and postnatal outcomes, including fetal growth restriction. As the placenta plays a critical role in the development of preeclampsia, surveying genomic features of the placenta, including expression of imprinted genes, may reveal molecular markers that can further refine subtypes to aid targeted disease management. In this study, we conducted a comprehensive survey of placental imprinted gene expression across early and late onset preeclampsia cases and preterm and term normotensive controls. Placentas were collected at delivery from women recruited at the Magee-Womens Hospital prenatal clinics, and expression levels were profiled across 109 imprinted genes. We observed downregulation of placental Mesoderm-specific transcript (MEST) and Necdin (NDN) gene expression levels (false discovery rate (FDR) < 0.05) among early onset preeclampsia cases compared to preterm controls. No differences in placental imprinted gene expression were observed between late onset preeclampsia cases and term controls. While few studies have linked NDN to pregnancy complications, reductions in MEST expression levels, as observed in our study, are consistently reported in the literature in relation to various pregnancy complications, including fetal growth restriction, suggesting a potential role for placental MEST expression as a biosensor of an adverse in utero environment.

Download Full-text

Placental imprinted gene expression mediates the effects of maternal psychosocial stress during pregnancy on fetal growth

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174418000545 ◽

2019 ◽

Vol 10 (02) ◽

pp. 196-205

Author(s):

L. Lambertini ◽

Q. Li ◽

Y. Ma ◽

W. Zhang ◽

K. Hao ◽

...

Keyword(s):

Gene Expression ◽

Fetal Growth ◽

Psychosocial Stress ◽

Imprinted Genes ◽

Economic Determinants ◽

Imprinted Gene ◽

Infant Gender ◽

Maternal Resources ◽

Gestational Age At Birth ◽

Lower Birthweight

AbstractImprinted genes uniquely drive and support fetoplacental growth by controlling the allocation of maternal resources to the fetus and affecting the newborn’s growth. We previously showed that alterations of the placental imprinted gene expression are associated with suboptimal perinatal growth and respond to environmental stimuli including socio-economic determinants. At the same time, maternal psychosocial stress during pregnancy (MPSP) has been shown to affect fetal growth. Here, we set out to test the hypothesis that placental imprinted gene expression mediates the effects of MPSP on fetal growth in a well-characterized birth cohort, the Stress in Pregnancy (SIP) Study. We observed that mothers experiencing high MPSP deliver infants with lower birthweight (P=0.047). Among the 109 imprinted genes tested, we detected panels of placental imprinted gene expression of 23 imprinted genes associated with MPSP and 26 with birthweight. Among these genes, five imprinted genes (CPXM2, glucosidase alpha acid (GAA), GPR1, SH3 and multiple ankyrin repeat domains 2 (SHANK2) and THSD7A) were common to the two panels. In multivariate analyses, controlling for maternal age and education and gestational age at birth and infant gender, two genes, GAA and SHANK2, each showed a 22% mediation of MPSP on fetal growth. These data provide new insights into the role that imprinted genes play in translating the maternal stress message into a fetoplacental growth pattern.

Download Full-text

Zfp57 inactivation illustrates the role of ICR methylation in imprinted gene expression during neural differentiation of mouse ESCs

Scientific Reports ◽

10.1038/s41598-021-93297-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Basilia Acurzio ◽

Ankit Verma ◽

Alessia Polito ◽

Carlo Giaccari ◽

Francesco Cecere ◽

...

Keyword(s):

Gene Expression ◽

Neural Differentiation ◽

Embryonic Stem ◽

Imprinted Genes ◽

Wild Type ◽

Mouse Escs ◽

Biallelic Expression ◽

Imprinted Gene ◽

Expression Levels ◽

Mutant Cells

AbstractZFP57 is required to maintain the germline-marked differential methylation at imprinting control regions (ICRs) in mouse embryonic stem cells (ESCs). Although DNA methylation has a key role in genomic imprinting, several imprinted genes are controlled by different mechanisms, and a comprehensive study of the relationship between DMR methylation and imprinted gene expression is lacking. To address the latter issue, we differentiated wild-type and Zfp57-/- hybrid mouse ESCs into neural precursor cells (NPCs) and evaluated allelic expression of imprinted genes. In mutant NPCs, we observed a reduction of allelic bias of all the 32 genes that were imprinted in wild-type cells, demonstrating that ZFP57-dependent methylation is required for maintaining or acquiring imprinted gene expression during differentiation. Analysis of expression levels showed that imprinted genes expressed from the non-methylated chromosome were generally up-regulated, and those expressed from the methylated chromosome were down-regulated in mutant cells. However, expression levels of several imprinted genes acquiring biallelic expression were not affected, suggesting the existence of compensatory mechanisms that control their RNA level. Since neural differentiation was partially impaired in Zfp57-mutant cells, this study also indicates that imprinted genes and/or non-imprinted ZFP57-target genes are required for proper neurogenesis in cultured ESCs.

Download Full-text

Effects of Plasma Choline Concentrations on Placental Development and Fetal Growth, With Potential Mechanistic Roles of Imprinted Genes

Current Developments in Nutrition ◽

10.1093/cdn/nzab046_052 ◽

2021 ◽

Vol 5 (Supplement_2) ◽

pp. 755-755

Author(s):

Olivia Gutherz ◽

Jia Chen ◽

Qian Li ◽

Maya Deyssenroth ◽

Neil Dodge ◽

...

Keyword(s):

Gene Expression ◽

Drug Use ◽

Fetal Growth ◽

Regression Models ◽

Alcohol Exposure ◽

Interaction Effects ◽

Placental Weight ◽

Imprinted Genes ◽

Placental Development ◽

Imprinted Gene

Abstract Objectives Imprinted genes are epigenetically regulated and play critical roles in placental development and fetal growth. We aimed to examine (1) the impact of maternal one-carbon (methyl donor) nutrition on placental imprinted gene expression, placental development, and fetal growth; (2) whether imprinted gene expression alterations mediate effects of one-carbon nutrition on placental development and fetal growth; (3) interaction effects between one-carbon nutrients and imprinted genes in placental development and fetal growth. Methods Histopathology and expression of 109 imprinted genes (Nanostring) were assessed in placentas from 101 women recruited at initiation of antenatal care in a prospective cohort study examining developmental effects of prenatal alcohol exposure in South Africa. Women were interviewed prenatally about demographics, alcohol, smoking, and drug use, and erythrocyte folate, serum vitamin B12, and plasma choline concentrations were assayed at recruitment. Infant weight and height were assessed at age 2 wk. Results In limma tests, women with plasma choline concentrations below the median had lower placental expression of EPS15, IGF2R, LINC00657, SGCE, ZC3H12C, and ZNF264 than women above the median (p < .05, FDR < .10). In regression models adjusted for potential confounders (maternal age, gravidity, education, alcohol and drug use), plasma choline (μM) was associated with larger placental weight (g) (B = 14.0(1.9, 26.2)) and reduced maternal vascular underperfusion (MVU) prevalence (B = −.07(−.12, −.02). In causal inference analyses, there were trends for mediation of the relation between choline and MVU by decreased LINC00657, ZC3H12C, and ZNF264 expression. In regression models examining plasma choline X imprinted gene expression interaction effects, choline modified relations of EPS15, ZC3H12C, and ZNF264 to placental weight and fetal growth. Conclusions Maternal plasma choline was associated with decreased placental expression of 6 imprinted genes, 3 of which may mediate effects of choline on placental development. Choline modified effects of 3 genes on placental and fetal growth. These findings suggest maternal choline status may impact placental and fetal development, with imprinted genes playing mechanistic roles. Funding Sources NIH/NIAAA; Lycaki-Young Fund.

Download Full-text

Molecular mechanisms of genomic imprinting and clinical implications for cancer

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399410001717 ◽

2011 ◽

Vol 13 ◽

Cited By ~ 53

Author(s):

Santiago Uribe-Lewis ◽

Kathryn Woodfine ◽

Lovorka Stojic ◽

Adele Murrell

Keyword(s):

Gene Expression ◽

Genomic Imprinting ◽

Noncoding Rna ◽

Molecular Mechanisms ◽

Expression Patterns ◽

Early Event ◽

Imprinted Genes ◽

Epigenetic Changes ◽

Imprinted Gene ◽

Growth Loss

Genomic imprinting is an epigenetic marking of genes in the parental germline that ensures the stable transmission of monoallelic gene expression patterns in a parent-of-origin-specific manner. Epigenetic marking systems are thus able to regulate gene activity independently of the underlying DNA sequence. Several imprinted gene products regulate cell proliferation and fetal growth; loss of their imprinted state, which effectively alters their dosage, might promote or suppress tumourigenic processes. Conversely, global epigenetic changes that underlie tumourigenesis might affect imprinted gene expression. Here, we review imprinted genes with regard to their roles in epigenetic predisposition to cancer, and discuss acquired epigenetic changes (DNA methylation, histone modifications and chromatin conformation) either as a result of cancer or as an early event in neoplasia. We also address recent work showing the potential role of noncoding RNA in modifying chromatin and affecting imprinted gene expression, and summarise the effects of loss of imprinting in cancer with regard to the roles that imprinted genes play in regulating growth signalling cascades. Finally, we speculate on the clinical applications of epigenetic drugs in cancer.

Download Full-text

Maternal prenatal depression is associated with decreased placental expression of the imprinted gene PEG3

Psychological Medicine ◽

10.1017/s0033291716001598 ◽

2016 ◽

Vol 46 (14) ◽

pp. 2999-3011 ◽

Cited By ~ 21

Author(s):

A. B. Janssen ◽

L. E. Capron ◽

K. O'Donnell ◽

S. J. Tunster ◽

P. G. Ramchandani ◽

...

Keyword(s):

Gene Expression ◽

Maternal Depression ◽

Fetal Growth ◽

Fetal Growth Restriction ◽

Growth Restriction ◽

Prenatal Depression ◽

Placental Lactogen ◽

Maternal Behaviour ◽

Imprinted Genes ◽

Neurodevelopmental Outcomes

BackgroundMaternal prenatal stress during pregnancy is associated with fetal growth restriction and adverse neurodevelopmental outcomes, which may be mediated by impaired placental function. Imprinted genes control fetal growth, placental development, adult behaviour (including maternal behaviour) and placental lactogen production. This study examined whether maternal prenatal depression was associated with aberrant placental expression of the imprinted genes paternally expressed gene 3 (PEG3), paternally expressed gene 10 (PEG10), pleckstrin homology-like domain family a member 2 (PHLDA2) and cyclin-dependent kinase inhibitor 1C (CDKN1C), and resulting impaired placental human placental lactogen (hPL) expression.MethodA diagnosis of depression during pregnancy was recorded from Manchester cohort participants’ medical notes (n = 75). Queen Charlotte's (n = 40) and My Baby and Me study (MBAM) (n = 81) cohort participants completed the Edinburgh Postnatal Depression Scale self-rating psychometric questionnaire. Villous trophoblast tissue samples were analysed for gene expression.ResultsIn a pilot study, diagnosed depression during pregnancy was associated with a significant reduction in placental PEG3 expression (41%, p = 0.02). In two further independent cohorts, the Queen Charlotte's and MBAM cohorts, placental PEG3 expression was also inversely associated with maternal depression scores, an association that was significant in male but not female placentas. Finally, hPL expression was significantly decreased in women with clinically diagnosed depression (44%, p < 0.05) and in those with high depression scores (31% and 21%, respectively).ConclusionsThis study provides the first evidence that maternal prenatal depression is associated with changes in the placental expression of PEG3, co-incident with decreased expression of hPL. This aberrant placental gene expression could provide a possible mechanistic explanation for the co-occurrence of maternal depression, fetal growth restriction, impaired maternal behaviour and poorer offspring outcomes.

Download Full-text

Genomic Imprinting of Dopa decarboxylase in Heart and Reciprocal Allelic Expression with Neighboring Grb10

Molecular and Cellular Biology ◽

10.1128/mcb.00862-07 ◽

2007 ◽

Vol 28 (1) ◽

pp. 386-396 ◽

Cited By ~ 28

Author(s):

Trevelyan R. Menheniott ◽

Kathryn Woodfine ◽

Reiner Schulz ◽

Andrew J. Wood ◽

David Monk ◽

...

Keyword(s):

Genomic Imprinting ◽

Promoter Region ◽

Germ Line ◽

Differential Methylation ◽

Dopa Decarboxylase ◽

Imprinted Genes ◽

Chromosome 11 ◽

Imprinted Gene ◽

Line Methylation ◽

Intron 1

ABSTRACT By combining a tissue-specific microarray screen with mouse uniparental duplications, we have identified a novel imprinted gene, Dopa decarboxylase (Ddc), on chromosome 11. Ddc_exon1a is a 2-kb transcript variant that initiates from an alternative first exon in intron 1 of the canonical Ddc transcript and is paternally expressed in trabecular cardiomyocytes of the embryonic and neonatal heart. Ddc displays tight conserved linkage with the maternally expressed and methylated Grb10 gene, suggesting that these reciprocally imprinted genes may be coordinately regulated. In Dnmt3L mutant embryos that lack maternal germ line methylation imprints, we show that Ddc is overexpressed and Grb10 is silenced. Their imprinting is therefore dependent on maternal germ line methylation, but the mechanism at Ddc does not appear to involve differential methylation of the Ddc_exon1a promoter region and may instead be provided by the oocyte mark at Grb10. Our analysis of Ddc redefines the imprinted Grb10 domain on mouse proximal chromosome 11 and identifies Ddc_exon1a as the first example of a heart-specific imprinted gene.

Download Full-text

Genomic imprinting and its role in ethiology of human hereditary diseases

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2004-3-8-17 ◽

2004 ◽

Vol 3 (3) ◽

pp. 8-17

Author(s):

S. A. Nazarenko

Keyword(s):

Gene Expression ◽

Genomic Imprinting ◽

Special Class ◽

Growth And Development ◽

Epigenetic Inheritance ◽

Hereditary Diseases ◽

Parental Origin ◽

Imprinted Genes ◽

Methylation Of Dna ◽

Differential Gene

Genomic imprinting is a form of non-Mendelian epigenetic inheritance that is defined by differential gene expression depending on its parental origin — maternal or paternal. It is known about 60 imprinted genes many of which effect significantly on the fetus growth and development. Methylation of DNA cytosine bases that defines the interaction of DNA and proteins identifying the modified bases and controls the gene expression through chromatin compacting-decompacting mechanism, is a main epigenetic genom modifier. Disturbances in monoallelic gene expression lead to the development of a special class of human hereditary diseases — genomic imprinting diseases.

Download Full-text

DNA demethylase ROS1 negatively regulates the imprinting of DOGL4 and seed dormancy in Arabidopsis thaliana

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1812847115 ◽

2018 ◽

Vol 115 (42) ◽

pp. E9962-E9970 ◽

Cited By ~ 15

Author(s):

Haifeng Zhu ◽

Wenxiang Xie ◽

Dachao Xu ◽

Daisuke Miki ◽

Kai Tang ◽

...

Keyword(s):

Gene Expression ◽

Seed Dormancy ◽

Genomic Imprinting ◽

Dna Demethylation ◽

Paternal Allele ◽

Maternal Allele ◽

Imprinted Gene ◽

Differential Gene ◽

Parent Of Origin ◽

Dna Demethylase

Genomic imprinting is a form of epigenetic regulation resulting in differential gene expression that reflects the parent of origin. In plants, imprinted gene expression predominantly occurs in the seed endosperm. Maternal-specific DNA demethylation by the DNA demethylase DME frequently underlies genomic imprinting in endosperm. Whether other more ubiquitously expressed DNA demethylases regulate imprinting is unknown. Here, we found that the DNA demethylase ROS1 regulates the imprinting of DOGL4. DOGL4 is expressed from the maternal allele in endosperm and displays preferential methylation and suppression of the paternal allele. We found that ROS1 negatively regulates imprinting by demethylating the paternal allele, preventing its hypermethylation and complete silencing. Furthermore, we found that DOGL4 negatively affects seed dormancy and response to the phytohormone abscisic acid and that ROS1 controls these processes by regulating DOGL4. Our results reveal roles for ROS1 in mitigating imprinted gene expression and regulating seed dormancy.

Download Full-text