X chromosome inactivation and genomic imprinting are classic epigenetic processes that cause disease when not appropriately regulated in mammals. Whereas X chromosome inactivation evolved to solve ...the problem of gene dosage, the purpose of genomic imprinting remains controversial. Nevertheless, the two phenomena are united by allelic control of large gene clusters, such that only one copy of a gene is expressed in every cell. Allelic regulation poses significant challenges because it requires coordinated long-range control in cis and stable propagation over time. Long noncoding RNAs have emerged as a common theme, and their contributions to diseases of imprinting and the X chromosome have become apparent. Here, we review recent advances in basic biology, the connections to disease, and preview potential therapeutic strategies for future development.
Exposure to endocrine disruptors is associated with developmental defects. One compound of concern, to which humans are widely exposed, is bisphenol A (BPA). In model organisms, BPA exposure is ...linked to metabolic disorders, infertility, cancer, and behavior anomalies. Recently, BPA exposure has been linked to DNA methylation changes, indicating that epigenetic mechanisms may be relevant. We investigated effects of exposure on genomic imprinting in the mouse as imprinted genes are regulated by differential DNA methylation and aberrant imprinting disrupts fetal, placental, and postnatal development. Through allele-specific and quantitative real-time PCR analysis, we demonstrated that maternal BPA exposure during late stages of oocyte development and early stages of embryonic development significantly disrupted imprinted gene expression in embryonic day (E) 9.5 and 12.5 embryos and placentas. The affected genes included Snrpn, Ube3a, Igf2, Kcnq1ot1, Cdkn1c, and Ascl2; mutations and aberrant regulation of these genes are associated with imprinting disorders in humans. Furthermore, the majority of affected genes were expressed abnormally in the placenta. DNA methylation studies showed that BPA exposure significantly altered the methylation levels of differentially methylated regions (DMRs) including the Snrpn imprinting control region (ICR) and Igf2 DMR1. Moreover, exposure significantly reduced genome-wide methylation levels in the placenta, but not the embryo. Histological and immunohistochemical examinations revealed that these epigenetic defects were associated with abnormal placental development. In contrast to this early exposure paradigm, exposure outside of the epigenetic reprogramming window did not cause significant imprinting perturbations. Our data suggest that early exposure to common environmental compounds has the potential to disrupt fetal and postnatal health through epigenetic changes in the embryo and abnormal development of the placenta.
Genomic imprinting refers to an epigenetic mark that distinguishes parental alleles and results in a monoallelic, parental-specific expression pattern in mammals. Few phenomena in nature depend more ...on epigenetic mechanisms while at the same time evading them. The alleles of imprinted genes are marked epigenetically at discrete elements termed imprinting control regions (ICRs) with their parental origin in gametes through the use of DNA methylation, at the very least. Imprinted gene expression is subsequently maintained using noncoding RNAs, histone modifications, insulators, and higher-order chromatin structure. Avoidance is manifest when imprinted genes evade the genome-wide reprogramming that occurs after fertilization and remain marked with their parental origin. This review summarizes what is known about the establishment and maintenance of imprinting marks and discusses the mechanisms of imprinting in clusters. Additionally, the evolution of imprinted gene clusters is described. While considerable information regarding epigenetic control of imprinting has been obtained recently, much remains to be learned.
DNA methylation is a major epigenetic mechanism for gene silencing. Whereas methyltransferases mediate cytosine methylation, it is less clear how unmethylated regions in mammalian genomes are ...protected from de novo methylation and whether an active demethylating activity is involved. Here, we show that either knockout or catalytic inactivation of the DNA repair enzyme thymine DNA glycosylase (TDG) leads to embryonic lethality in mice. TDG is necessary for recruiting p300 to retinoic acid (RA)-regulated promoters, protection of CpG islands from hypermethylation, and active demethylation of tissue-specific developmentally and hormonally regulated promoters and enhancers. TDG interacts with the deaminase AID and the damage response protein GADD45a. These findings highlight a dual role for TDG in promoting proper epigenetic states during development and suggest a two-step mechanism for DNA demethylation in mammals, whereby 5-methylcytosine and 5-hydroxymethylcytosine are first deaminated by AID to thymine and 5-hydroxymethyluracil, respectively, followed by TDG-mediated thymine and 5-hydroxymethyluracil excision repair.
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► Inactivation of TDG leads to embryonic lethality and altered DNA methylation patterns ► TDG keeps CpG islands unmethylated and actively demethylates promoters and enhancers ► TDG interacts with AID and GADD45a and regulates the levels of AID ► TDG removes 5-hydromethyluracil originated by deamination of 5-hydroxymethylcytosine
Increasing evidence has highlighted the critical role of early life environment in shaping the future health outcomes of an individual. Moreover, recent studies have revealed that early life ...perturbations can affect the health of subsequent generations. Hypothesized mechanisms of multi- and transgenerational inheritance of abnormal developmental phenotypes include epigenetic misregulation in germ cells. In this review, we will focus on the available data demonstrating the ability of endocrine disrupting chemicals (EDCs), including bisphenol A (BPA), phthalates, and parabens, to alter epigenetic marks in rodents and humans. These epigenetic marks include DNA methylation, histone post-translational modifications, and non-coding RNAs. We also review the current evidence for multi- and transgenerational inheritance of abnormal developmental changes in the offspring following EDC exposure. Based on published results, we conclude that EDC exposure can alter the mouse and human epigenome, with variable tissue susceptibilities. Although increasing data suggest that exposure to EDCs is linked to transgenerational inheritance of reproductive, metabolic, or neurological phenotypes, more studies are needed to validate these observations and to elucidate further whether these developmental changes are directly associated with the relevant epigenetic alterations.
Genes that are subject to genomic imprinting in mammals are preferentially expressed from a single parental allele. This imprinted expression of a small number of genes is crucial for normal ...development, as these genes often directly regulate fetal growth. Recent work has also demonstrated intricate roles for imprinted genes in the brain, with important consequences on behavior and neuronal function. Finally, new studies have revealed the importance of proper expression of specific imprinted genes in induced pluripotent stem cells and in adult stem cells. As we review here, these findings highlight the complex nature and developmental importance of imprinted genes.
Genomic imprinting in mammals Barlow, Denise P; Bartolomei, Marisa S
Cold Spring Harbor perspectives in biology,
2014-Feb-01, 2014-02-01, 20140201, Letnik:
6, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Genomic imprinting affects a subset of genes in mammals and results in a monoallelic, parental-specific expression pattern. Most of these genes are located in clusters that are regulated through the ...use of insulators or long noncoding RNAs (lncRNAs). To distinguish the parental alleles, imprinted genes are epigenetically marked in gametes at imprinting control elements through the use of DNA methylation at the very least. Imprinted gene expression is subsequently conferred through lncRNAs, histone modifications, insulators, and higher-order chromatin structure. Such imprints are maintained after fertilization through these mechanisms despite extensive reprogramming of the mammalian genome. Genomic imprinting is an excellent model for understanding mammalian epigenetic regulation.
DNA methylation is an essential epigenetic mark crucial for normal mammalian development. This modification controls the expression of a unique class of genes, designated as imprinted, which are ...expressed monoallelically and in a parent-of-origin-specific manner. Proper parental allele-specific DNA methylation at imprinting control regions (ICRs) is necessary for appropriate imprinting. Processes that deregulate DNA methylation of imprinted loci cause disease in humans. DNAmethylation patterns dramatically change duringmammalian development: first, the majority of the genome, with the exception of ICRs, is demethylated after fertilization, and subsequently undergoes genome-wide de novo DNA methylation. Secondly, after primordial germ cells are specified in the embryo, another wave of demethylation occurs, with ICR demethylation occurring late in the process. Lastly, ICRs reacquire DNA methylation imprints in developing germ cells. We describe the past discoveries and current literature defining these crucial dynamics in relation to imprinted genes and the rest of the genome. Summary Sentence This review summarizes the changes in DNA methylation at imprinting control regions, which regulate monoallelic imprinted gene expression, from fertilization, embryogenesis, and PGC development, which are essential for proper development.
Genomic imprinting, a phenomenon in which the two parental alleles are regulated differently, is observed in mammals, marsupials and a few other species, including seed-bearing plants. Dysregulation ...of genomic imprinting can cause developmental disorders such as Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). In this Review, we discuss (1) how various (epi)genetic lesions lead to the dysregulation of clinically relevant imprinted loci, and (2) how such perturbations may contribute to the developmental defects in BWS and SRS. Given that the regulatory mechanisms of most imprinted clusters are well conserved between mice and humans, numerous mouse models of BWS and SRS have been generated. These mouse models are key to understanding how mutations at imprinted loci result in pathological phenotypes in humans, although there are some limitations. This Review focuses on how the biological findings obtained from innovative mouse models explain the clinical features of BWS and SRS.
About the Authors: Marisa S. Bartolomei * E-mail: bartolom@pennmedicine.upenn.edu Affiliation: Epigenetics Institute, Department of Cell and Developmental Biology, Perelman School of Medicine, ...University of Pennsylvania, Philadelphia, Pennsylvania, United States of America ORCID logo http://orcid.org/0000-0001-9410-5222 Rebecca J. Oakey Affiliation: Department of Medical & Molecular Genetics, King’s College London, London, United Kingdom ORCID logo http://orcid.org/0000-0003-2706-8139 Anton Wutz Affiliation: D-BIOL, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland ORCID logo http://orcid.org/0000-0002-4377-6330 Citation: Bartolomei MS, Oakey RJ, Wutz A (2020) Genomic imprinting: ...their regulation may differ from genes that are imprinted in the soma. In this collection, Courtney Hannah discusses the function and regulation of imprinted genes in the placenta, with special consideration given to the role of endogenous retroviruses (ERVs) in mediating placental-specific imprinting 8. Because of the unusual nature of imprinting, the identification and study of imprinted genes have driven the adaption and modification of methods and, in some cases, necessitated the development of new technology. Additionally, nuclear transplantation, haploid embryonic stem cells combined with site-directed deletions have more recently shown that the main block to uniparental embryo development is caused by imprinted gene expression.