Genome-wide studies have revealed that mammalian genomes are pervasively transcribed. This has led to the identification and isolation of novel classes of non-coding RNAs (ncRNAs) that influence gene expression by a variety of mechanisms. Here we review the characteristics and functions of regulatory ncRNAs in chromatin remodelling and at multiple levels of transcriptional and post-transcriptional regulation. We also describe the potential roles of ncRNAs in vascular biology and in mediating epigenetic modifications that might play roles in cardiovascular disease susceptibility. The emerging recognition of the diverse functions of ncRNAs in regulation of gene expression suggests that they may represent new targets for therapeutic intervention.

Non-coding RNAs as regulators of gene expression and epigenetics.

Adverse influences during fetal life alter the structure and function of distinct cells, organ systems or homoeostatic pathways, thereby 'programming' the individual for an increased risk of developing cardiovascular disease and diabetes in adult life. Fetal programming can be caused by a number of different perturbations in the maternal compartment, such as altered maternal nutrition and reduced utero-placental blood flow; however, the underlying mechanisms remain to be fully established. Perturbations in the maternal environment must be transmitted across the placenta in order to affect the fetus. Here, we review recent insights into how the placenta responds to changes in the maternal environment and discuss possible mechanisms by which the placenta mediates fetal programming. In IUGR (intrauterine growth restriction) pregnancies, the increased placental vascular resistance subjects the fetal heart to increased work load, representing a possible direct link between altered placental structure and fetal programming of cardiovascular disease. A decreased activity of placental 11beta-HSD-2 (type 2 isoform of 11beta-hydroxysteroid dehydrogenase) activity can increase fetal exposure to maternal cortisol, which programmes the fetus for later hypertension and metabolic disease. The placenta appears to function as a nutrient sensor regulating nutrient transport according to the ability of the maternal supply line to deliver nutrients. By directly regulating fetal nutrient supply and fetal growth, the placenta plays a central role in fetal programming. Furthermore, perturbations in the maternal compartment may affect the methylation status of placental genes and increase placental oxidative/nitrative stress, resulting in changes in placental function. Intervention strategies targeting the placenta in order to prevent or alleviate altered fetal growth and/or fetal programming include altering placental growth and nutrient transport by maternally administered IGFs (insulin-like growth factors) and altering maternal levels of methyl donors.

Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches

Associations between maternal obesity and adverse fetal outcomes are well documented, but the mechanisms involved are largely unknown. Most previous work has focused on postconceptional events, however, our laboratory has shown pre- and periconceptional aberrations in maternal glucose metabolism have adverse effects on oocytes and embryos that carry on to the fetus. To demonstrate effects of maternal obesity in the pre- and periconceptional periods, we compared reproductive tissues from diet-induced obese female mice to those of control mice. Ovaries were either stained for follicular apoptosis or dissected and evaluated for oocyte size and meiotic maturation. Mice were also mated and followed for reproductive outcomes including preimplantation embryonic IGF-I receptor (IGF-IR) immunostaining, midgestation fetal growth, and midgestational placental IGF receptor 2 (Igf2r) mRNA. Delivered pups were followed for growth and development of markers of metabolic syndrome. Compared with controls, obese mice had significantly more apoptotic ovarian follicles, smaller and fewer mature oocytes, decreased embryonic IGF-IR staining, smaller fetuses, increased placental Igf2r mRNA, and smaller pups. All weaned pups were fed a regular diet. At 13 wk pups delivered from obese mice were significantly larger, and these pups demonstrated glucose intolerance and increased cholesterol and body fat suggesting early development of a metabolic-type syndrome. Together, our findings suggest maternal obesity has adverse effects as early as the oocyte and preimplantation embryo stage and that these effects may contribute to lasting morbidity in offspring, underscoring the importance of optimal maternal weight and nutrition before conception.

Diet-Induced Obesity Model: Abnormal Oocytes and Persistent Growth Abnormalities in the Offspring

BACKGROUND Most reproductive failures originate during the periconceptional period and are influenced by the age and the lifestyle of parents-to-be. We advance the hypothesis that these failures can arise as a partial consequence of derangements to one-carbon (1-C) metabolism (i.e. metabolic pathways that utilize substrates/cofactors such as methionine, vitamin B12, folate). 1-C metabolic pathways drive the synthesis of proteins, biogenic amines and lipids required for early growth, together with the synthesis and methylation of DNA and histones essential for the regulation of gene expression. We review how deficiencies in periconceptional 1-C metabolism affect fertility and development together with underlying mechanisms derived from animal studies. METHODS A literature search was performed using PubMed and bibliographies of all relevant original research articles and reviews. RESULTS We define 'periconception' as a 5-6-month period in women embracing oocyte growth, fertilization, conceptus formation and development to Week 10 of gestation (coinciding with the closure of the secondary palate in the embryo). During this period significant epigenetic modifications to chromatin occur that correspond with normal development. Subtle variations in 1-C metabolism genes and deficiencies in 1-C substrates/cofactors together with poor lifestyle, such as smoking and alcohol consumption, disturb 1-C metabolism and contribute to subfertility and early miscarriage and compromise offspring health. Procedures used in assisted reproduction can also disturb these metabolic pathways and contribute to poor pregnancy outcomes. CONCLUSIONS Evidence presented indicates that parental nutrition and other lifestyle factors during the periconceptional period can affect reproductive performance via 1-C metabolic pathways. This knowledge provides opportunities for treatment and prevention of reproductive failures and future non-communicable diseases.

/pdf/the-periconceptional-period-reproduction-and-long-term-21k4r0wr3t.pdf

The periconceptional period, reproduction and long-term health of offspring: the importance of one-carbon metabolism

Poor maternal nutrition during pregnancy can alter postnatal phenotype and increase susceptibility to adult cardiovascular and metabolic diseases. However, underlying mechanisms are largely unknown. Here, we show that maternal low protein diet (LPD), fed exclusively during mouse preimplantation development, leads to offspring with increased weight from birth, sustained hypertension, and abnormal anxiety-related behavior, especially in females. These adverse outcomes were interrelated with increased perinatal weight being predictive of later adult overweight and hypertension. Embryo transfer experiments revealed that the increase in perinatal weight was induced within blastocysts responding to preimplantation LPD, independent of subsequent maternal environment during later pregnancy. We further identified the embryo-derived visceral yolk sac endoderm (VYSE) as one mediator of this response. VYSE contributes to fetal growth through endocytosis of maternal proteins, mainly via the multiligand megalin (LRP2) receptor and supply of liberated amino acids. Thus, LPD maintained throughout gestation stimulated VYSE nutrient transport capacity and megalin expression in late pregnancy, with enhanced megalin expression evident even when LPD was limited to the preimplantation period. Our results demonstrate that in a nutrient-restricted environment, the preimplantation embryo activates physiological mechanisms of developmental plasticity to stablize conceptus growth and enhance postnatal fitness. However, activation of such responses may also lead to adult excess growth and cardiovascular and behavioral diseases.

https://bioone.org/journals/Biology-of-Reproduction/volume-78/issue-2/biolreprod.107.064220/Adaptive-Responses-by-Mouse-Early-Embryos-to-Maternal-Diet-Protect/10.1095/biolreprod.107.064220.pdf

Adaptive Responses by Mouse Early Embryos to Maternal Diet Protect Fetal Growth but Predispose to Adult Onset Disease

In our previous study, we have shown that maternal low protein diet (LPD, 9% casein vs 18% casein control) fed exclusively during the rat preimplantation period (0–4.25 day postcoitum) induced low birth weight, altered postnatal growth and hypertension in a gender-specific manner. In this study, we investigated the effect of maternal LPD restricted only to the preimplantation period (switched diet) or provided throughout gestation on fetal growth and imprinted gene expression in blastocyst and fetal stages of development. Male, but not female, blastocysts collected from LPD dams displayed a significant reduction (30%) in H19 mRNA level. A significant reduction in H19 (9.4%) and Igf2 (10.9%) mRNA was also observed in male, but not in female, fetal liver at day 20 postcoitum in response to maternal LPD restricted to the preimplantation period. No effect on the blastocyst expression of Igf2R was observed in relation to maternal diet. The reduction in H19 mRNA expression did not correlate with an observed alteration in DNA methylation at the H19 differentially methylated region in fetal liver. In contrast, maternal LPD throughout 20 days of gestation did not affect male or female H19 and Igf2 imprinted gene expression in fetal liver. Neither LPD nor switched diet treatments affected H19 and Igf2 imprinted gene expression in day 20 placenta. Our findings demonstrate that one contributor to the alteration in postnatal growth induced by periconceptional maternal LPD may derive from a gender-specific programming of imprinted gene expression originating within the preimplantation embryo itself.

/pdf/imprinted-gene-expression-in-the-rat-embryo-fetal-axis-is-3erx28icxd.pdf

Imprinted gene expression in the rat embryo–fetal axis is altered in response to periconceptional maternal low protein diet

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Imprinted gene expression in the rat embryo–fetal axis is altered in response to periconceptional maternal low protein diet