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Genomic Imprinting and the Regulation of Growth and Metabolism

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A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (15 March 2021) | Viewed by 45894

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Special Issue Editors

Dr. Miguel Constancia

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Guest Editor

Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, Department of Obstetrics and Gynaecology, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 0SW, UK
Interests: epigenetics of growth and metabolism; genomic imprinting and the regulation of resource allocation

Dr. Marika Charalambous

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Guest Editor

Department of Medical and Molecular Genetics, Faculty of Life Sciences & Medicine King’s College London, Strand London WC2R 2LS, UK
Interests: endocrine communication between mother and offspring during pregnancy; developmental regulation of metabolic axes by imprinted genes

Dr. Ionel Sandovici

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Guest Editor

Metabolic Research Laboratories, Medical Research Council Metabolic Diseases Unit, Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, UK
Interests: epigenetic mechanisms in developmental programming of adult disease; physiological roles of insulin-like growth factors in pregnancy

Prof. Dr. Eamonn Maher

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Department of Medical Genetics, University of Cambridge, and NIHR Cambridge Biomedical Research Centre, Cambridge CB2 OQQ, UK
Interests: molecular basis of inherited forms of renal cell carcinoma, phaeochromocytoma, multiple primary cancers, genomic imprinting disorders, and developmental disorders

Special Issue Information

Dear Colleagues,

Genomic imprinting refers to parent-of-origin-specific epigenetic modifications of the genome. Since its discovery in the early 1980s, this intriguing biological phenomenon has captivated the interest of scientists and the wider public. This is mainly because of the uniqueness of epigenetic regulation at imprinted loci and the phylogenetic distribution of imprinting, which is principally restricted to placental mammals and plants with endosperm, giving rise to a number of evolutionary theories. Genomic imprinting is highly relevant to a number of aspects in biomedical research, from embryogenesis, growth control and energy homeostasis, to brain development and behavior. When deregulated, imprinted genes can cause human congenital disorders affecting development, growth, and metabolism, as well as increasing the risk for specific forms of cancer. Thus, it is important to understand the growth and metabolic pathways under the control of imprinted genes, at cellular, tissue, and organismic level. Whilst it is well established that imprinted genes affect prenatal and postnatal growth, and metabolism, it is less clear how growth is linked to metabolism.

The aim of this Special Issue is to provide novel insights into the roles of imprinted genes in regulation of developmental growth and metabolism. Topics to be addressed include but are not limited to imprinted genes and the allocation of maternal resources (e.g., imprinting in placenta, imprinting in lactation), role of imprinting in regulation of glucose and fat metabolism, imprinted genes in central regulation of growth and metabolism, imprinting in human disorders of growth and metabolism, role of imprinted genes as candidates in developmental programming of adult disease, relationships between fetal nutrient acquisition and postnatal metabolism driven by imprinted genes, and the roles of imprinted genes in cellular signaling and molecular metabolism.

Dr. Miguel Constancia
Dr. Marika Charalambous
Dr. Ionel Sandovici
Prof. Eamonn Maher
Guest Editors

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Keywords

Genomic imprinting
Metabolism
Growth
Placenta
Lactation
Cell signalling
Cellular metabolism

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Published Papers (11 papers)

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Research

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13 pages, 603 KiB

Open AccessArticle

Deletion of the Imprinted Phlda2 Gene Increases Placental Passive Permeability in the Mouse

by Emily Angiolini, Ionel Sandovici, Philip M. Coan, Graham J. Burton, Colin P. Sibley, Abigail L. Fowden and Miguel Constância

Genes 2021, 12(5), 639; https://doi.org/10.3390/genes12050639 - 25 Apr 2021

Cited by 4 | Viewed by 3219

Abstract

Genomic imprinting, an epigenetic phenomenon that causes the expression of a small set of genes in a parent-of-origin-specific manner, is thought to have co-evolved with placentation. Many imprinted genes are expressed in the placenta, where they play diverse roles related to development and nutrient supply function. However, only a small number of imprinted genes have been functionally tested for a role in nutrient transfer capacity in relation to the structural characteristics of the exchange labyrinthine zone. Here, we examine the transfer capacity in a mouse model deficient for the maternally expressed Phlda2 gene, which results in placental overgrowth and a transient reduction in fetal growth. Using stereology, we show that the morphology of the labyrinthine zone in Phlda2^−/+ mutants is normal at E16 and E19. In vivo placental transfer of radiolabeled solutes ¹⁴C-methyl-D-glucose and ¹⁴C-MeAIB remains unaffected at both gestational time points. However, placental passive permeability, as measured using two inert hydrophilic solutes (¹⁴C-mannitol; ¹⁴C-inulin), is significantly higher in mutants. Importantly, this increase in passive permeability is associated with fetal catch-up growth. Our findings uncover a key role played by the imprinted Phlda2 gene in modifying placental passive permeability that may be important for determining fetal growth. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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11 pages, 1564 KiB

Open AccessArticle

Maternal Uniparental Disomy of Chromosome 20 (UPD(20)mat) as Differential Diagnosis of Silver Russell Syndrome: Identification of Three New Cases

by Pierpaola Tannorella, Daniele Minervino, Sara Guzzetti, Alessandro Vimercati, Luciano Calzari, Giuseppa Patti, Mohamad Maghnie, Anna Elsa Maria Allegri, Donatella Milani, Giulietta Scuvera, Milena Mariani, Piergiorgio Modena, Angelo Selicorni, Lidia Larizza and Silvia Russo

Genes 2021, 12(4), 588; https://doi.org/10.3390/genes12040588 - 17 Apr 2021

Cited by 12 | Viewed by 3644

Abstract

Silver Russell Syndrome (SRS, MIM #180860) is a rare growth retardation disorder in which clinical diagnosis is based on six features: pre- and postnatal growth failure, relative macrocephaly, prominent forehead, body asymmetry, and feeding difficulties (Netchine–Harbison clinical scoring system (NH-CSS)). The molecular mechanisms consist in (epi)genetic deregulations at multiple loci: the loss of methylation (LOM) at the paternal H19/IGF2:IG-DMR (chr11p15.5) (50%) and the maternal uniparental disomy of chromosome 7 (UPD(7)mat) (10%) are the most frequent causes. Thus far, about 40% of SRS remains undiagnosed, pointing to the need to define the rare mechanisms in such a consistent fraction of unsolved patients. Within a cohort of 176 SRS with an NH-CSS ≥ 3, a molecular diagnosis was disclosed in about 45%. Among the remaining patients, we identified in 3 probands (1.7%) with UPD(20)mat (Mulchandani–Bhoj–Conlin syndrome, OMIM #617352), a molecular mechanism deregulating the GNAS locus and described in 21 cases, characterized by severe feeding difficulties associated with failure to thrive, preterm birth, and intrauterine/postnatal growth retardation. Our patients share prominent forehead, feeding difficulties, postnatal growth delay, and advanced maternal age. Their clinical assessment and molecular diagnostic flowchart contribute to better define the characteristics of this rare imprinting disorder and to rank UPD(20)mat as the fourth most common pathogenic molecular defect causative of SRS. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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10 pages, 2346 KiB

Open AccessArticle

Mosaic Segmental and Whole-Chromosome Upd(11)mat in Silver-Russell Syndrome

by Laura Pignata, Angela Sparago, Orazio Palumbo, Elena Andreucci, Elisabetta Lapi, Romano Tenconi, Massimo Carella, Andrea Riccio and Flavia Cerrato

Genes 2021, 12(4), 581; https://doi.org/10.3390/genes12040581 - 16 Apr 2021

Cited by 6 | Viewed by 2723

Abstract

Molecular defects altering the expression of the imprinted genes of the 11p15.5 cluster are responsible for the etiology of two congenital disorders characterized by opposite growth disturbances, Silver–Russell syndrome (SRS), associated with growth restriction, and Beckwith–Wiedemann syndrome (BWS), associated with overgrowth. At the molecular level, SRS and BWS are characterized by defects of opposite sign, including loss (LoM) or gain (GoM) of methylation at the H19/IGF2:intergenic differentially methylated region (H19/IGF2:IG-DMR), maternal or paternal duplication (dup) of 11p15.5, maternal (mat) or paternal (pat) uniparental disomy (upd), and gain or loss of function mutations of CDKN1C. However, while upd(11)pat is found in 20% of BWS cases and in the majority of them it is segmental, upd(11)mat is extremely rare, being reported in only two SRS cases to date, and in both of them is extended to the whole chromosome. Here, we report on two novel cases of mosaic upd(11)mat with SRS phenotype. The upd is mosaic and isodisomic in both cases but covers the entire chromosome in one case and is restricted to 11p14.1-pter in the other case. The segmental upd(11)mat adds further to the list of molecular defects of opposite sign in SRS and BWS, making these two imprinting disorders even more specular than previously described. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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31 pages, 3418 KiB

Open AccessArticle

Dynamic Expression of Imprinted Genes in the Developing and Postnatal Pituitary Gland

by Valeria Scagliotti, Ruben Esse, Thea L. Willis, Mark Howard, Isabella Carrus, Emily Lodge, Cynthia L. Andoniadou and Marika Charalambous

Genes 2021, 12(4), 509; https://doi.org/10.3390/genes12040509 - 30 Mar 2021

Cited by 8 | Viewed by 5271

Abstract

In mammals, imprinted genes regulate many critical endocrine processes such as growth, the onset of puberty and maternal reproductive behaviour. Human imprinting disorders (IDs) are caused by genetic and epigenetic mechanisms that alter the expression dosage of imprinted genes. Due to improvements in diagnosis, increasing numbers of patients with IDs are now identified and monitored across their lifetimes. Seminal work has revealed that IDs have a strong endocrine component, yet the contribution of imprinted gene products in the development and function of the hypothalamo-pituitary axis are not well defined. Postnatal endocrine processes are dependent upon the production of hormones from the pituitary gland. While the actions of a few imprinted genes in pituitary development and function have been described, to date there has been no attempt to link the expression of these genes as a class to the formation and function of this essential organ. This is important because IDs show considerable overlap, and imprinted genes are known to define a transcriptional network related to organ growth. This knowledge deficit is partly due to technical difficulties in obtaining useful transcriptomic data from the pituitary gland, namely, its small size during development and cellular complexity in maturity. Here we utilise high-sensitivity RNA sequencing at the embryonic stages, and single-cell RNA sequencing data to describe the imprinted transcriptome of the pituitary gland. In concert, we provide a comprehensive literature review of the current knowledge of the role of imprinted genes in pituitary hormonal pathways and how these relate to IDs. We present new data that implicate imprinted gene networks in the development of the gland and in the stem cell compartment. Furthermore, we suggest novel roles for individual imprinted genes in the aetiology of IDs. Finally, we describe the dynamic regulation of imprinted genes in the pituitary gland of the pregnant mother, with implications for the regulation of maternal metabolic adaptations to pregnancy. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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11 pages, 1272 KiB

Open AccessArticle

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

by Maya A. Deyssenroth, Qian Li, Carlos Escudero, Leslie Myatt, Jia Chen and James M. Roberts

Genes 2020, 11(10), 1146; https://doi.org/10.3390/genes11101146 - 29 Sep 2020

Cited by 9 | Viewed by 2491

Abstract

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. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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18 pages, 1275 KiB

Open AccessArticle

The Evolution of Imprinted microRNAs and Their RNA Targets

by David Haig and Avantika Mainieri

Genes 2020, 11(9), 1038; https://doi.org/10.3390/genes11091038 - 3 Sep 2020

Cited by 8 | Viewed by 3319

Abstract

Mammalian genomes contain many imprinted microRNAs. When an imprinted miRNA targets an unimprinted mRNA their interaction may have different fitness consequences for the loci encoding the miRNA and mRNA. In one possible outcome, the mRNA sequence evolves to evade regulation by the miRNA by a simple change of target sequence. Such a response is unavailable if the targeted sequence is strongly constrained by other functions. In these cases, the mRNA evolves to accommodate regulation by the imprinted miRNA. These evolutionary dynamics are illustrated using the examples of the imprinted C19MC cluster of miRNAs in primates and C2MC cluster in mice that are paternally expressed in placentas. The 3′ UTR of PTEN, a gene with growth-related and metabolic functions, appears to be an important target of miRNAs from both clusters. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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Review

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33 pages, 525 KiB

Open AccessReview

DNA Methylation Dynamics in the Female Germline and Maternal-Effect Mutations That Disrupt Genomic Imprinting

by Zahra Anvar, Imen Chakchouk, Hannah Demond, Momal Sharif, Gavin Kelsey and Ignatia B. Van den Veyver

Genes 2021, 12(8), 1214; https://doi.org/10.3390/genes12081214 - 6 Aug 2021

Cited by 29 | Viewed by 7095

Abstract

Genomic imprinting is an epigenetic marking process that results in the monoallelic expression of a subset of genes. Many of these ‘imprinted’ genes in mice and humans are involved in embryonic and extraembryonic growth and development, and some have life-long impacts on metabolism. During mammalian development, the genome undergoes waves of (re)programming of DNA methylation and other epigenetic marks. Disturbances in these events can cause imprinting disorders and compromise development. Multi-locus imprinting disturbance (MLID) is a condition by which imprinting defects touch more than one locus. Although most cases with MLID present with clinical features characteristic of one imprinting disorder. Imprinting defects also occur in ‘molar’ pregnancies-which are characterized by highly compromised embryonic development-and in other forms of reproductive compromise presenting clinically as infertility or early pregnancy loss. Pathogenic variants in some of the genes encoding proteins of the subcortical maternal complex (SCMC), a multi-protein complex in the mammalian oocyte, are responsible for a rare subgroup of moles, biparental complete hydatidiform mole (BiCHM), and other adverse reproductive outcomes which have been associated with altered imprinting status of the oocyte, embryo and/or placenta. The finding that defects in a cytoplasmic protein complex could have severe impacts on genomic methylation at critical times in gamete or early embryo development has wider implications beyond these relatively rare disorders. It signifies a potential for adverse maternal physiology, nutrition, or assisted reproduction to cause epigenetic defects at imprinted or other genes. Here, we review key milestones in DNA methylation patterning in the female germline and the embryo focusing on humans. We provide an overview of recent findings regarding DNA methylation deficits causing BiCHM, MLID, and early embryonic arrest. We also summarize identified SCMC mutations with regard to early embryonic arrest, BiCHM, and MLID. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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23 pages, 1813 KiB

Open AccessReview

Environmental Exposure to Endocrine Disrupting Chemicals Influences Genomic Imprinting, Growth, and Metabolism

by Nicole Robles-Matos, Tre Artis, Rebecca A. Simmons and Marisa S. Bartolomei

Genes 2021, 12(8), 1153; https://doi.org/10.3390/genes12081153 - 28 Jul 2021

Cited by 22 | Viewed by 4867

Abstract

Genomic imprinting is an epigenetic mechanism that results in monoallelic, parent-of-origin-specific expression of a small number of genes. Imprinted genes play a crucial role in mammalian development as their dysregulation result in an increased risk of human diseases. DNA methylation, which undergoes dynamic changes early in development, is one of the epigenetic marks regulating imprinted gene expression patterns during early development. Thus, environmental insults, including endocrine disrupting chemicals during critical periods of fetal development, can alter DNA methylation patterns, leading to inappropriate developmental gene expression and disease risk. Here, we summarize the current literature on the impacts of in utero exposure to endocrine disrupting chemicals on genomic imprinting and metabolism in humans and rodents. We evaluate how early-life environmental exposures are a potential risk factor for adult metabolic diseases. We also introduce our mouse model of phthalate exposure. Finally, we describe the potential of genomic imprinting to serve as an environmental sensor during early development and as a novel biomarker for postnatal health outcomes. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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16 pages, 9573 KiB

Open AccessReview

Growth Restriction and Genomic Imprinting-Overlapping Phenotypes Support the Concept of an Imprinting Network

by Thomas Eggermann, Justin H. Davies, Maithé Tauber, Erica van den Akker, Anita Hokken-Koelega, Gudmundur Johansson and Irène Netchine

Genes 2021, 12(4), 585; https://doi.org/10.3390/genes12040585 - 17 Apr 2021

Cited by 24 | Viewed by 5552

Abstract

Intrauterine and postnatal growth disturbances are major clinical features of imprinting disorders, a molecularly defined group of congenital syndromes caused by molecular alterations affecting parentally imprinted genes. These genes are expressed monoallelically and in a parent-of-origin manner, and they have an impact on human growth and development. In fact, several genes with an exclusive expression from the paternal allele have been shown to promote foetal growth, whereas maternally expressed genes suppress it. The evolution of this correlation might be explained by the different interests of the maternal and paternal genomes, aiming for the conservation of maternal resources for multiple offspring versus extracting maximal maternal resources. Since not all imprinted genes in higher mammals show the same imprinting pattern in different species, the findings from animal models are not always transferable to human. Therefore, human imprinting disorders might serve as models to understand the complex regulation and interaction of imprinted loci. This knowledge is a prerequisite for the development of precise diagnostic tools and therapeutic strategies for patients affected by imprinting disorders. In this review we will specifically overview the current knowledge on imprinting disorders associated with growth retardation, and its increasing relevance in a personalised medicine direction and the need for a multidisciplinary therapeutic approach. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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11 pages, 2807 KiB

Open AccessCase Report

Paternal Uniparental Disomy of the Entire Chromosome 20 in a Child with Beckwith-Wiedemann Syndrome

by Sanaa Choufani, Jung Min Ko, Youliang Lou, Cheryl Shuman, Leona Fishman and Rosanna Weksberg

Genes 2021, 12(2), 172; https://doi.org/10.3390/genes12020172 - 27 Jan 2021

Cited by 4 | Viewed by 2712

Abstract

Epigenetic alterations at imprinted genes on different chromosomes have been linked to several imprinting disorders (IDs) such as Beckwith-Wiedemann syndrome (BWS) and pseudohypoparathyroidism type 1b (PHP1b). Here, we present a male patient with these two distinct IDs caused by two independent mechanisms-loss of methylation (LOM) at chromosome 11p15.5 associated with multi-locus imprinting disturbances (MLID and paternal uniparental disomy of chromosome 20 (patUPD20). A clinical diagnosis of BWS was made based on the clinical features of macrosomia, macroglossia, and umbilical hernia. The diagnosis of PHP1b was supported by the presence of reduced growth velocity and mild learning disability as well as hypocalcemia and hyperphosphatemia at 14 years of age. Molecular analyses, including genome-wide DNA methylation (Illumina 450k array), bisulfite pyrosequencing, single nucleotide polymorphism (SNP) array and microsatellite analysis, demonstrated loss of methylation (LOM) at IC2 on chromosome 11p15.5, and paternal isodisomy of the entire chromosome 20. In addition, imprinting disturbances were noted at the differentially methylated regions (DMRs) associated with DIRAS3 on chromosome 1 and PLAGL1 on chromosome 6. This is the first case report of PHP1b due to patUPD20 diagnosed in a BWS patient with LOM at IC2 demonstrating etiologic heterogeneity for multiple imprinting disorders in a single individual. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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9 pages, 2399 KiB

Open AccessCase Report

Novel Variant in PLAG1 in a Familial Case with Silver–Russell Syndrome Suspicion

by Yerai Vado, Arrate Pereda, Isabel Llano-Rivas, Nerea Gorria-Redondo, Ignacio Díez and Guiomar Perez de Nanclares

Genes 2020, 11(12), 1461; https://doi.org/10.3390/genes11121461 - 5 Dec 2020

Cited by 13 | Viewed by 3496

Abstract

Silver–Russell syndrome (SRS) is a rare growth-related genetic disorder that is mainly associated with prenatal and postnatal growth retardation. Molecular causes are not clear in all cases, the most common ones being loss of methylation on chromosome 11p15 (≈50%) and maternal uniparental disomy for chromosome 7 (upd(7)mat) (≈10%). However, pathogenic variants in genes such as CDKN1C, HMGA2, IGF2, or PLAG1 have also been described. Previously, two families and one sporadic case have been reported with PLAG1 alterations. Here, we present a case of a female with clinical suspicion of SRS (i.e., intrauterine and postnatal growth retardation, triangular face, psychomotor delay, speech delay, feeding difficulties). No alterations in methylation or copy number were detected at chromosomes 11p15 and 7 using methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The custom panel study by next-generation sequencing (NGS) revealed a frameshift variant in the PLAG1 gene (NM_002655.3:c.551delA; p.(Lys184Serfs *45)). Familial studies confirmed that the variant was inherited from the mother and it was also present in other family members. New evidence of pathogenic alterations in the HMGA2-PLAG1-IGF2 pathway suggest the importance of studying and taking into account these genes as alternative molecular causes of Silver–Russell syndrome. Full article

(This article belongs to the Special Issue Genomic Imprinting and the Regulation of Growth and Metabolism)

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