The disruption of genomic imprinting leads to largely established human diseases with recognizable clinical features such as Beckwith-Wiedemann syndrome (MIM 130,650), Silver-Russell syndrome (MIM 180,860), Prader-Willi syndrome (MIM 176,270), and Angelman syndrome (MIM 105,830), but less dramatic and more subtle changes in the imprinted patterns, especially concerning multi-locus imprinting disturbances (MLID), can instead modulate fetal growth, resource acquisition, and organogenesis [4446]. Mattick JS, Makunin IV (2006) Non-coding RNA. Further processes of vascular remodeling, trophoblastic cellular migration, and immune regulation allow the formation of the placenta, a transient organ that connects the fetus to the mother [103]. In conclusion, even if the placenta is a temporary organ, there is no doubt that its alterations can strongly influence the development of the fetus, and in particular of the fetal brain. Keywords: Maternal GDM can create different effects like global DNA hypermethylation or alteration of miRNA expressions. It is the comments and import statements in the code base of DNA. Gil-Ibez P, Bernal J, Morte B. Thyroid hormone regulation of gene expression in primary cerebrocortical cells: role of thyroid hormone receptor subtypes and interactions with retinoic acid and glucocorticoids. The epigenetic modulation of gene expression begins in the gametes and zygote through genomic imprinting and then continues throughout the whole gestation with changes to the fetal and maternal methyloma and the specific action of the ncRNA system. ncRNAs were originally thought to be only involved in gene expression at the post-transcriptional level, while nowadays ithas been largely established that non-coding RNAs function as the most common regulatory RNAs, both at pre and post transcriptional level (e.g., by promoter silencing or RNA interference mechanisms), and are also involved in epigenetic control. HHS Vulnerability Disclosure, Help Nutrients. In human cell lines, PCB exposure has been shown to modulate the activity of histone demethylases via androgen receptor binding [156]. Xia W, Xie W. Rebooting the epigenomes during mammalian early embryogenesis. The plausibility of maternal nutritional status being a contributing factor to the risk for fetal alcohol spectrum disorders: the potential influence of zinc status as an example. Accessibility WebEpigenetics is the study of non-genotoxic, reversible, heritable mechanisms that influence gene expression without changing the DNA sequence. Epigenetic: New Insight in Gestational Diabetes Mellitus Gueta K, Molotski N, Gerchikov N, Mor E, Savion S, Fein A, Toder V, Shomron N, Torchinsky A. Teratogen-induced alterations in microRNA-34, microRNA-125b and microRNA-155 expression: correlation with embryonic p53 genotype and limb phenotype. A cross-study analysis of prenatal exposures to environmental contaminants and the epigenome: support for stress-responsive transcription factor occupancy as a mediator of gene-specific CpG methylation patterning. Best JD, Carey N. The epigenetics of normal pregnancy. The earliest stages of embryonic development are characterized by major epigenetic remodeling events that include parental DNA methylation erasure and reprogramming (with the exception of DMRs), chromatin folding establishment, and spatial reorganization of the genome [6567]. The epigenetic code is determined by several mechanisms that affect gene expression, the most well-known of which is DNA methylation (See Figure 1). doi: 10.3390/cells8121559. Faa G, Manchia M, Pintus R, Gerosa C, Marcialis MA, Fanos V. Fetal programming of neuropsychiatric disorders. HTR2A methylation correlates inversely with infant quality of movement, but positively with infant attention [125]. Hot spots of epigenetic action. Keen CL, Uriu-Adams JY, Skalny A, Grabeklis A, Grabeklis S, Green K, Yevtushok L, Wertelecki WW, Chambers CD. Epigenetics of recurrent pregnancy loss - eBioMedicine These placental modifications can range from alterations in aspects of macroscopic placental morphology to more subtle changes in placental gene expression which may have long-term effect on offspring health. Stage 1: from gametes to embryo-endometrium cross-talk; Stage 2: from placenta-fetus cross-talk to brain development, with an overview on environmental factors as well (nutrition and teratogens). As a result, DNA methylation is mainly restricted to the transcribed gene bodies, while intergenic regions are hypomethylated [5759], as non-CpG hypermethylation plays an active role in gene expression regulation during oocyte maturation, potentially through the incorporation with transcription factors [57]. The developing brain tissue requires considerable nutritional intake and it is particularly susceptible to overabundance or insufficiency of specific nutrients and growth factors [108, 110, 111]. Main epigenetic processes involved in the regulation of pregnancy, -Transcription silencing (sporadically transcription permissive), -Protein recruitment (scaffolding &/or sponging), DNMT, DNA methyltransferase; TET, ten-eleven translocation methylcytosine dioxygenases; MBD4, methyl-CpG binding protein 4; TDG, thymine DNAglycosylase; (A), acetylation; (M), methylation; (P), phosphorylation; (U), ubiquitination; HATs, histone acetyltransferases; HDACs, histone deacetylases; HMTs, histone methyltransferases; HDMs, histone demethylases; DUBs, deubiquitinating enzymes; ncRNAs, non-coding RNAs; sncRNAs, short ncRNAs; siRNAs, short interfering RNAs; miRNAs, microRNAs; piRNAs, piwi interacting RNAs; lncRNAs, long ncRNAs; lincRNAs, long intergenic ncRNAs; ilncRNAs, intronic long ncRNAs; eRNAs, enhancer long ncRNAs; DMRs, differentially methylated regions; ICRs, imprinting control regions. Maternal overeating and low protein consumption during pregnancy is associated with significant miRNA dysregulation in the offspring tissue, which may be associated with chronic inflammation status and metabolic health in offspring as early as the weaning age [145, 146]. Zhao L-Y, Song J, Liu Y, Song C-X, Yi C. Mapping the epigenetic modifications of DNA and RNA. Walln E, Auvinen P, Kaminen-Ahola N. The effects of early prenatal alcohol exposure on epigenome and embryonic development. Many researches have also found that alcohol interferes with gene expression levels and epigenetic processes by altering DNA methylation (particularly the expression of two methyltransferase enzymes, DNMT1 and DNMT3A), histone regulation, and non-coding RNAs [162]. Lesseur C, Armstrong DA, Murphy MA, Appleton AA, Koestler DC, Paquette AG, Lester BM, Marsit CJ. Jaenisch R, Bird A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Numerous studies also managed to identify maternal effect genes (MEGs) which encode factors that are present in the oocyte and are required for embryonic development. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Altundag , elebi-Saltik B. Glaser J, Mundlos S (2021) 3D or not 3D: shaping the genome during development. These effects are regulated by alteration in theepigenetic programming. A better comprehension of the underlying mechanisms and their consequences could therefore improve diagnosis and treatment of human infertility and diseases. Borchiellini M, Ummarino S, Di Ruscio A. Would you like email updates of new search results? [93] found a total of 26 upregulated and 17 downregulated miRNAs following in vitro decidualization of hESC. Disclaimer. Pathological epigenetic alterations are particularly important in feto-materal medicine. Therefore, it is reasonable to assume that some neurobehavioral disorders (such as autism spectrum disorders, ASD) may originate from placental changes in the production of these metabolites. Shafique S, Winn LM. Mechanism for stable maintenance of gene expression that involves physically 'marking' DNA or its associated proteins. INTRODUCTION. Therefore, these epigenetic changes represent a critical mechanism essential to understand the changes of fetal epigenome causing adverse outcomes at birth and later in life, warranting further study. Additionally, some EDs are known to interact with one-carbon metabolism, which produces methyl donors used for DNA methylation [158]. Maccani MA, Padbury JF, Lester BM, Knopik VS, Marsit CJ. An ever-increasing amount of evidence suggests that such regulatory processes may play a pivotal role both in the initiation of pregnancy and in the later processes of embryonic and fetal development, thus determining long-term effects even in adult life. Some epigenetic tags remain in place as genetic On the other hand, poly-ubiquitination flags proteins as a mark for degradation or activation in some signaling pathways [22, 30]. Schmidt RJ, Schroeder DI, Crary-Dooley FK, Barkoski JM, Tancredi DJ, Walker CK, Ozonoff S, Hertz-Picciotto I, LaSalle JM. Expression of imprinted genes in placenta is associated with infant neurobehavioral development. Epub 2015 Sep 12. doi: 10.1152/ajpendo.00372.2015. Finally, regarding another known teratogen inducing limb reduction anomalies (5-aza-2-deoxycytidin or 5-aza), recent animal study focused the attention on miR-34 family, concluding that 5-aza and cyclophosphamide are able to activate miR-34 family in p53-independent fashion. Also, hEECs have been demonstrated to be able to uptake embryo-derived miRNAs, such as the embryoendometrial adhesion inhibitor miR-661 [101]. WebAbstract Rapidly growing evidences link maternal lifestyle and prenatal factors with serious health consequences and diseases later in life. Investigation towards miRNA and downstream transcriptional regulation are growing, while studies investigating histone modifications are still sparse [176]. Antonio Capalbo is full-time employee at Igenomix Italy. Histone modifications and their role in epigenetics of atopy and allergic diseases. In recent years, epigenetic changes traced to gestation have been linked, if tenuously, to a child's future risk of conditions ranging from obesity to asthma to poor response to stress. Epigenetics of pregnancy: looking beyond the DNA code Cai S, Qiu A, Broekman BFP, Wong EQ, Gluckman PD, Godfrey KM, Saw SM, Soh S-E, Kwek K, Chong Y-S, Meaney MJ, Kramer MS, Rifkin-Graboi A, GUSTO study group The influence of gestational diabetes on neurodevelopment of children in the first two years of life: a prospective study. Tochigi H, Kajihara T, Mizuno Y, Mizuno Y, Tamaru S, Kamei Y, Okazaki Y, Brosens JJ, Ishihara O. Placental miRNome studies have also demonstrated its importance towards the coordination and modulation of the placental transcriptome [110, 111]. Paquette AG, Chu T, Wu X, Wang K, Price ND, Sadovsky Y. We have therefore chosen the most significant steps and those for which there is already literature data that allow a reasoned review of the causative mechanism. Zheng J, Xiao X, Zhang Q, Wang T, Yu M, Xu J. Maternal low-protein diet modulates glucose metabolism and hepatic microRNAs expression in the early life of offspring . Epigenetics & Inheritance - University of Utah Embryoepithelium interactions during implantation at a glance. Napso T, Yong HEJ, Lopez-Tello J, Sferruzzi-Perri AN. Many signals regulate chromatin activation or repression; among these, those related to nutrient availability are relevant for epigenetic programming in the placenta. Epigenetics Zijlmans MAC, Riksen-Walraven JM, de Weerth C. Associations between maternal prenatal cortisol concentrations and child outcomes: a systematic review. The answer is epigenetics, a rapidly growing area of science that focuses on the processes that help direct when individual genes are turned on or off. Histone mono-ubiquitination has a crucial role in protein translocation, DNA damage signaling, and regulation of transcription. Hamza M, Halayem S, Mrad R, Bourgou S, Charfi F, Belhadj A. Encephale. The secretion of exosomes from the apical surface of endometrial glands, which was confirmed by electron microscopy, is consistent with the existence of endosomes in epithelial cells and of embryo-derived extracellular vesicles [100]. Other authors declare no conflicts of interest. Elbracht M, Mackay D, Begemann M, Kagan KO, Eggermann T. Disturbed genomic imprinting and its relevance for human reproduction: causes and clinical consequences. The https:// ensures that you are connecting to the Expression and trafficking of placental microRNAs at the feto-maternal interface. Khambata K, Raut S, Deshpande S, Mohan S, Sonawane S, Gaonkar R, Ansari Z, Datar M, Bansal V, Patil A, Warke H, Balasinor NH. Roseboom TJ, van der Meulen JH, Osmond C, Barker DJ, Ravelli AC, Schroeder-Tanka JM, van Montfrans GA, Michels RP, Bleker OP. Garry D. Lasaga 4K views38 slides. Extracellular vesicles: novel regulators of conceptus-uterine interactions? Liu H-Y, Liu S-M, Zhang Y-Z. The understanding of the genetics and the epigenetics of the disease is still at infancy with several missing links. 10.18632/aging.102864. It has been suggested that high levels of let-7 in the receptive uterus could be important for differentiation of a receptive endometrium [87]. GDM changes also placental microbiota: for example, in women with GDM, there are less bacteria belonging to the Pseudomonadales order and Acinetobacter genus associated with a more adverse metabolic and inflammatory phenotype. To date, the relationship between placental metabolism and epigenetic programming has been especially studied in animals (and only marginally in humans) with particular attention to sex development, as sex differences in epigenetic mechanisms such as DNA methylation have been described across placental development. Epigenetic regulation during early embryogenesis - Epigenetic regulation during early embryogenesis reprogramming and remodelling Helena Fulkova Istitute of Animal Science, www.vuzv.cz helena PowerPoint PPT presentation | free to view Diabetes in Pregnancy - Embryogenesis. Introduction Gestational diabetes mellitus (GDM), defined as a glucose Cratty MS, Ward HE, Johnson EA, Azzaro AJ, Birkle DL. Epigenetics: Expert Knopik VS, Marceau K, Bidwell LC, Rolan E. Prenatal substance exposure and offspring development: does DNA methylation play a role? Retis-Resendiz AM, Gonzlez-Garca IN, Len-Jurez M, Camacho-Arroyo I, Cerbn M, Vzquez-Martnez ER. However, specific differentially methylated regions (DMRs), in which DNA is methylated on one specific parental allele, escape the reprogramming process that happens in the pre-implantation embryo [37]. Casati L, Sendra R, Poletti A, Negri-Cesi P, Celotti F. Androgen receptor activation by polychlorinated biphenyls: epigenetic effects mediated by the histone demethylase Jarid1b. Hjort L, Martino D, Grunnet LG, Naeem H, Maksimovic J, Olsson AH, Zhang C, Ling C, Olsen SF, Saffery R, Vaag AA. In multicellular eukaryotes, DNA methylation mostly occurs at cytosines of CpG (CphosphateG) dinucleotides; highly methylated sequences can also be found in satellite DNAs, repetitive element and non-repetitive intergenic DNA. Epigenetics and Pregnancy: Conditional Snapshot or Rolling Event. Casati L, Sendra R, Sibilia V, Celotti F. Endocrine disrupters: the new players able to affect the epigenome. These compounds exhibit weak steroid-like activity and therefore can affect reproductive development along multiple points including the hypothalamus and the gonad. In humans, excess amounts of corticotropin releasing hormones (CRH) and cortisol reaching the fetal brain can alter personality and predispose to attention deficits and depressive illness through changes in neurotransmitter activity [9, 73]. Hansel, Gretel, and the consequences of failing to remove histone methylation breadcrumbs. Bonnin A, Goeden N, Chen K, Wilson ML, King J, Shih JC, Blakely RD, Deneris ES, Levitt P. A transient placental source of serotonin for the fetal forebrain. While it is known that most human transcripts are not translated, many of them actively participate in essential cellular functions nonetheless. The epigenomic changes, due to prenatal exposure to ED, include altered global DNA methylation, gene specific CpG methylation, and microRNA expression [155]. She displayed tongue fasciculations and muscle atrophy. Such a brief but crucial phase represents a window of vulnerability towards interfering maternal and environmental factors (such as chronic metabolic disorders, polycystic ovary syndrome, diet, and teratogen exposure), as highlighted by an ever-increasing number of studies [6871]. An official website of the United States government. Epigenetics is the branch of genetics that studies the different mechanisms that influence gene expression without direct modification of the DNA sequence. Epigenetics can be defined as somatically heritable states of gene expression resulting from changes in chromatin structure without alterations in the DNA sequence, including DNA methylation, histone modifications, and chromatin remodeling. BMJ. Hot spots of epigenetic action. in pregnancy Pathogenic variants in MEGs or the absence of MEG factors are correlated to adverse outcomes, like zygotic cleavage failure, imprinting disorders, and structural birth defects [6264]. Lifestyle, pregnancy and epigenetic effects - PubMed The term decidualization defines the functional and morphological transition of the endometrial cells to form the cellular environment into which the blastocyst is able to implantitself. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new Knfler M, Haider S, Saleh L, Pollheimer J, Gamage TKJB, James J. Human placenta and trophoblast development: key molecular mechanisms and model systems. Gannon JR, Emery BR, Jenkins TG, Carrell DT. Kalish JM, Jiang C, Bartolomei MS. Epigenetics and imprinting in human disease. The initial steps of nervous system development start as early as 23weeks post fertilization in humans; however, neuronal proliferation begins later in the first trimester and synaptogenesis and neural migration mainly occur in the later stages of pregnancy, during the second and third trimesters. Meng H, Cao Y, Qin J, Song X, Zhang Q, Shi Y, Cao L. DNA methylation, its mediators and genome integrity. Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W, Walter J, Surani MA. 2016 May 15;310(10):E797-810. Epigenetics is concerned with this regulation. Despite several differences and significant variability, probably attributable to decidualization in vitro, these studies have nonetheless shown that the miRNA profiles of the proliferative versus secretory endometrium are significantly different, and therefore deserving of further research. and transmitted securely. Associations of existing diabetes, gestational diabetes, and glycosuria with offspring IQ and educational attainment: the Avon Longitudinal Study of Parents and Children. In vitro studies showed that stress hormones can increase excitability hippocampal cells [131]. Cannarella R, Crafa A, Condorelli RA, Mongio LM, La Vignera S, Calogero AE. FOIA Working toward a transdisciplinary approach to teaching and learning planetary health-A collective reflection. Homer H, Rice GE, Salomon C. Review: Embryo- and endometrium-derived exosomes and their potential role in assisted reproductive treatments-liquid biopsies for endometrial receptivity. This narrative review aims to recapitulate both the already established and the newly emerging environmental and parental factors that regulate pregnancy through epigenetic mechanisms. Lussier AA, Bodnar TS, Mingay M, Morin AM, Hirst M, Kobor MS, Weinberg J. Prenatal alcohol exposure: profiling developmental DNA methylation patterns in central and peripheral tissues. DNA methylation profiles may not persist into adulthood but could alter developmental trajectories and induce lasting alterations in brain structure, connectivity, and function [163]. DNA methylation dynamics in the female germline and maternal-effect mutations that disrupt genomic imprinting. Epigenetics Paul Magbanua 54.2K views63 slides. Extensive evidence has progressively emerged that the gestational environment determines a remarkable impact on an epigenetic level, at least with two different mechanisms: by directly regulating the stages of implantation and placentation; and widely remodeling epigenetic patterns during prenatal development, thus determining long-term outcomes in the offspring [4, 5, 710]. The modulation of immune response is considered an important target for miRNAs, because major histocompatibility complexes such as HLA-G appear to be extensively regulated by noncoding RNAs such as miR-133a [87, 88]. Epigenetics in fertilization and preimplantation embryo development. However, a recent review concluded that most of the published papers on this topic did not reveal a significant association between maternal cortisol in pregnancy and poorer offspring birth outcomes, lower cognitive outcomes, lower cognitive/motor development, or more behavioral problems in infancy and childhood. The placenta is known to be involved in the transfer of nutrients, hormones, and metabolites, but it is important to remember that it also produces neurotransmitters, including serotonin (5-HT), dopamine (DA), norepinephrine/epinephrine, which enter the maternalfetal circulation and interact with the development of the fetal brain. Maternal effect genes: update and review of evidence for a link with birth defects. While the cells One of the mostcommon pregnancy complications worldwide correlated to nutrition is gestational diabetes (GDM). Received 2021 Nov 22; Accepted 2022 Mar 1. Figure1 details the main hot spots, divided into stage 1 (from gametes to embryo-endometrium cross-talk) and stage 2 (from placenta-fetus cross-talk to brain development, with an overview on environmental factors as well). Endocrine disruptors (EDs), for example, are environmental pollutants that mimic endogenous hormonal signals. official website and that any information you provide is encrypted Stage 1: from gametes to embryo-endometrium cross-talk; Stage 2: from placenta-fetus cross-talk to brain development, with an overview on environmental factors as well (nutrition and teratogens). Inter- and transgenerational epigenetic inheritance: evidence in Chen J, Xue Y. Epigenetics Front Neuroendocrinol. Extravillous trophoblast and decidual natural killer cells: a remodelling partnership. WebEpigenetics: Introduction and Definition and the mechanism Mohit Adhikary 24.5K views52 slides. Am J Physiol Regul Integr Comp Physiol. Human endometrial stem cells (hESC) have been decidualized in vitro to explore the effects of decidualization on miRNA expression. Pharmaceuticals (Basel). [3741]. After fertilization, oviductal and endometrial fluids nurture the embryo and regulate its development, before being replaced in this role by the placenta in the further stages of the pregnancy, while the embryo, and later the fetus, interact with the maternal environment in order to further its own implantation and development. For such reasons, it has been proposed that a contemporary definition of epigenetics should also include the gene silencing or upregulation mediated by ncRNAs [3436]. But this isn't completely true. Before Therefore, the recognition of relevant placental biomarkers, such as OGT and leptin, that, in response to maternal nutrition and stress hormones levels, produce epigenetic modifications which sensibly affect the neurodevelopmental programming, may allow in the future for a better understanding and prevention of neurodevelopmental disorders in the offspring [123].