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Journal ArticleDOI

Genomic imprinting disorders: lessons on how genome, epigenome and environment interact.

TL;DR: Interactions between the genome, the epigenome and the environment in germ cells and early embryos have an impact on developmental outcomes and on the heritability of imprinting disorders.
Abstract: Genomic imprinting, the monoallelic and parent-of-origin-dependent expression of a subset of genes, is required for normal development, and its disruption leads to human disease. Imprinting defects can involve isolated or multilocus epigenetic changes that may have no evident genetic cause, or imprinting disruption can be traced back to alterations of cis-acting elements or trans-acting factors that control the establishment, maintenance and erasure of germline epigenetic imprints. Recent insights into the dynamics of the epigenome, including the effect of environmental factors, suggest that the developmental outcomes and heritability of imprinting disorders are influenced by interactions between the genome, the epigenome and the environment in germ cells and early embryos.

Summary (2 min read)

Introduction

  • In therian mammals, a subset of autosomal genes is preferentially expressed from only one of the two parental chromosomes, some from the maternally inherited allele, others from the paternal allele1.
  • The authors begin with a brief overview of the genomic basis of imprinting and its control, before reviewing the lifecycle of genomic imprinting and how disruption of the individual factors involved in the establishment, maintenance and erasure of imprints can result in disease.
  • Transcription in oocytes is required for methylation at numerous gDMRs57, an act that may render the chromatin more accessible to the de novo methylation machinery and/or be associated with specific chromatin changes.
  • In both humans and mice, whereas most gDMRs lose DNA methylation in pre-implantation stages49,51, imprinting centres evade the embryonic wave of epigenetic reprogramming, and studies in both mouse models and human patients with rare imprinting disorders suggest they do so through interaction with critical factors expressed in the oocyte and early embryo. [H2].
  • Evidence for this comes from reports of preimplantation genetic diagnosis of embryos with maternal-effect NLRP7 mutations in which all cleavage-stage embryos arrested and had various maternal aneuploidies86.

Endocrine disruptors

  • In addition to micronutrient availability, prenatal exposure to estrogenic endocrine- disrupting compounds (EDC), such as bisphenol A (BPA), results in deregulation of genomic methylation and hydroxymethylation133,134, with imprinting and methylation anomalies being reported in both mouse placenta135 and developing gametes136,137.
  • In summary, combined genetic and environmental predispositions may erode the gametic and zygotic competence to reprogramme the epigenome, with consequences on imprint maintenance, and insights into these effects in humans may be gained by delineating the aetiology of apparently sporadic primary epimutations in individuals with imprinting disorders. [H1].
  • Some of the key factors and genomic sequences involved in this process have been identified, but the causation and timing of their interactions require further clarification.
  • Three therapeutic approaches for the neurological disorders AS and PWS have been proposed141-143.
  • Another exciting approach is the direct modification of epigenetic marks at imprinted genes using catalytically inactivated Cas9 (dCas9) fusion proteins.

KHDC3L/

  • Domain Containing 3 Like, Subcortical Maternal Complex Member Imprinting not assessed84 Biparental hydatidiform moles.
  • No pathogenic variants identified in MLID36,186 NLRP5/MATER Member of SCMC Imprinting not assessed82 MLID37 OOEP Member of SCMC Imprinting not assessed193 Single case of MLID39 PADI6 Member of SCMC Imprinting not assessed83 MLID39 ZAR1 Oocyte-specific zinc finger protein Imprinting not assessed194 Single case of MLID39 VEZF1 Zinc finger transcription factor DB1 Partial LOM at H19 and Igf2r gDMRs195.
  • Zinc finger protein GOM at Peg3 and GNAS203 not reported POU5F1 Pioneer pluripotency transcription factor Imprinting not assessed204 Binding site pathogenic variants leads to IC1 GOM in BWS99,205,206 SOX2 Pioneer pluripotency transcription factor Imprinting not assessed207 Binding site pathogenic variants leads to IC1 GOM in BWS99,103,205,206 PGCs, primordial germ cells.

Assisted reproductive technologies

  • Techniques used to achieve pregnancy during the treatment of infertility.
  • ART covers a wide spectrum of treatments including the use of fertility drugs, intrauterine insemination and in vitro fertilization/intracytoplasmic sperm injection.

Blastocyst

  • Developmental stage of mammalian embryo just before implantation consisting of an inner cell mass which will form the embryo, and a cavity with an outer layer called trophoblast, which will give rise to the placenta.
  • Cis-acting element DNA sequence regulating the expression of a gene that is present on the same chromosome.

Endogenous retrovirus

  • Repetitive genetic element present in the genome that, similarly to retroviruses, uses the activity of reverse transcriptase to move from one locus to another (also known as retrotransposons).
  • Epiallele Epigenetic profile which is maintained in somatic tissues resulting in interindividual variation.

Genome activation

  • The initiation of gene expression in the developing embryo.
  • The initial burst of expression is termed zygotic genome activation (ZGA) and is regulated by pioneer transcription factors during the oocyte-to-embryo transition.
  • Germline differentially methylated region (gDMR): Regions of differential DNA methylation between parental alleles in somatic cells that originate from the gametes.
  • GDMRs that survive embryonic reprogramming are generally associated with imprinted genes.

Hydatidiform mole

  • Benign gestational trophoblastic disease developing during pregnancy and resulting from an abnormal fertilization.
  • It is commonly sporadic and contains only sperm DNA.
  • Occasionally, it can be biparental, recurrent and familial following an autosomal recessive mode of inheritance.

Imprinting centre

  • A function definition for gDMRs that have been shown to regulate imprinted genes expression through either genetic targeting in mouse or through mutations in patients.
  • Also known as imprinting control region (ICR).
  • Not all gDMRs have been shown to be imprinting centre regions.

Multi-locus imprinting disturbance

  • Methylation anomalies at imprinted DMRs in patients with imprinting disorders in addition to those that are normally associated with the disease.
  • Maternal effect gene A gene coding for an oocyte-derived transcript or protein that is required for the early development of the embryo.

Protamines

  • Basic proteins that largely replace histones in the nucleus of mature sperm for more condensed DNA packaging.
  • Secondary differentially methylated region A region of differential DNA methylation between parental alleles that does not originate from the germline.

Subcortical maternal complex

  • A large multi-protein complex comprising of NLRP5, OOEP, TLE6, PADI6 and KHDC3L that localises to the outermost regions of the cytoplasm in oocytes and excluded from regions of cell-to-cell contact in cleavage embryos.
  • Trans-acting factor Protein regulating the expression of a gene.

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1
Genomic imprinting disorders: lessons on how genome, epigenome and
environment interact
David Monk
1
, Deborah J. G. Mackay
2
, Thomas Eggermann
3
, Eamonn R. Maher
4
and
Andrea Riccio
5*
1
Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical
Research Institute (IDIBELL), 08908 L'Hospitalet de Llobregat, Barcelona, Spain.
2
Human Genetics and Genomic Medicine, Faculty of Medicine University of
Southampton, Southampton, UK.
3
Institute of Human Genetics, Medical Faculty, RWTH Aachen University, Aachen,
Germany.
4
Department of Medical Genetics, University of Cambridge and NIHR Cambridge
Biomedical Research Centre, Cambridge, UK.
5
Department of Environmental, Biological and Pharmaceutical Sciences and
Technologies, University of Campania “Luigi Vanvitelli”, Caserta; Institute of
Genetics and Biophysics “Adriano Buzzati-Traverso”, CNR, Napoli, Italy.
*email: andrea.riccio@unicampania.it
Abstract |
Genomic imprinting, the monoallelic and parent-of-origin-dependent expression of a
subset of genes, is required for normal development. Its disruption leads to human
disease involving isolated or multi-locus epigenetic changes that can be traced back
to alterations of cis-acting sequences or trans-acting factors controlling the
establishment, maintenance and erasure of germline epigenetic imprints or may
have no evident genetic cause. Recent insights into the dynamics of the epigenome
including the effect of environmental factors suggest that the developmental
outcomes and heritability of imprinting disorders are influenced by interactions
between the genome, the epigenome and the environment in germ cells and early
embryos. In this Review, we discuss the latest advances in the study of genomic
imprinting, focusing on the imprinting life-cycle and its possible errors leading to
human diseases. We discuss the modes of inheritance of imprinting defects and

2
evidences from humans and animal models that environmental factors may influence
genomic imprinting. Finally, we highlight areas requiring additional research that
could complete our understanding of imprinting disorders, as well as new
technological advances that might correct imprinting errors.
Introduction
In therian mammals, a subset of autosomal genes is preferentially expressed from
only one of the two parental chromosomes, some from the maternally inherited
allele, others from the paternal allele
1
. This parental origin-dependent expression
results from differential epigenetic marking, primarily from methylated cytosine at
CpG dinucleotides of genes during gametogenesis in the male and female germline.
These genomic imprints endure for one generation, from their establishment in
mature germ cells of an individual to their erasure in the gamete precursors of their
progeny. Genomic imprinting thus represents a type of intergenerational epigenetic
inheritance. Of note, parent-of-origin-dependent methylation differs from sequence-
dependent allelic methylation, in which stochastic fluctuation between epialleles [G]
is influenced by genetic variants
2
.
In humans, approximately 100 imprinted genes have been identified
3-5
. Many
imprinted genes have important roles during human development, and alteration of
their expression and function can lead to imprinting disorders (Table 1), congenital
conditions with a lifelong impact on health and in some cases increased cancer risk
6
.
Molecular changes underlying imprinting disorders comprise genetic changes, such
as copy number variants (CNVs), uniparental disomy [G] (UPD), and pathogenic
gene sequence variants, or epigenetic changes that affect the regulation of imprinted
loci (epimutations [G]). The frequency of the four types of molecular alterations
varies markedly between different imprinting disorders, with the highest frequency of
epimutations in the chromosome 11p15-associated disorders Beckwith–Wiedemann
syndrome (BWS) and Silver–Russell syndrome (SRS)
7
. Epimutations that occur
without detectable DNA sequence changes are referred to as primary epimutations
and may represent random or environment-driven errors in the establishment or
maintenance of an epigenetic programme. By contrast, secondary epimutations arise
downstream from genetic changes that affect cis-acting elements or trans-acting

3
factors
8
. As normal imprinting marks once set persist throughout the life course of an
organism, similarly, imprinting errors originating in the germline as primary or
secondary epimutations
are permanently maintained in somatic tissues, resulting in
disease phenotypes later in development
. Primary or secondary epimutations (as well
as UPDs) that occur after fertilization can result in somatic mosaicism (Box 1).
Although genetic alterations and epimutations differ in their nature and aetiology,
they all disturb the fine-tuned balance of imprinted gene expression. In some cases,
loss of methylation (LOM) and gain of methylation (GOM) of the same imprinting
centre result in ‘mirror’ disorders that are broadly characterized by opposite clinical
features and gene expression patterns, for example, in the case of BWS and SRS
(Table 1 and Fig. 1)
7
.
Advances in whole-genome sequencing and single-cell genome-wide analysis are
driving the study of imprinting disorders arising from pathogenic variants that disrupt
key epigenetic reprogramming processes in early embryogenesis, shedding new
light on the dynamics of the epigenome as it passes from parents, through gametes,
to offspring. Furthermore, recent studies on the interaction between environment and
the epigenomes of gametes and early embryos suggest mechanistic explanations for
the sporadic occurrence of imprinting errors.
This Review focuses on imprints that effect essentially permanent and ubiquitous
(rather than tissue-specific or transient (Box 2)) changes on gene expression
potential at affected loci. We begin with a brief overview of the genomic basis of
imprinting and its control, before reviewing the lifecycle of genomic imprinting and
how disruption of the individual factors involved in the establishment, maintenance
and erasure of imprints can result in disease. Finally, we discuss the heritability of
imprinting defects and the role of environmental insults in imprinting disorders. For
details on the evolutionary significance of genomic imprinting
1,9
, the methods for
imprinting analysis
10
, the physiological role of imprinted genes
6
or the chromatin
mechanisms in imprinting
11
, the reader is referred to previous authoritative reviews.
[H1] The genomic basis of imprinting
The majority of imprinted genes are found in clusters, called imprinted domains,
which enables coordination via shared regulatory elements such as long non-coding
RNAs (lncRNAs) and differentially methylated regions (DMRs), where DNA
methylation differs between the maternally derived and paternally derived alleles.

4
Each imprinted domain is controlled by an independent ‘imprinting centre’, which is
generally characterized by a germline differentially methylated region (gDMR), also
known as primary DMR (Fig. 2). About 35 gDMRs associated with imprinted loci
have been identified in the human genome (Table 2)
12
. gDMRs are also
characterized by different chromatin configurations on parental chromosomes, with
histone marks characteristic of closed chromatin (for example, histone 3 lysine 9
dimethylation (H3K9me2), trimethylation (H3K9me3) and histone 4 lysine 20
trimethylation (H4K20me3)) on the methylated allele, and histone marks
characteristic of open chromatin (for example, H3K4me2 and H3K4me3) on the
unmethylated allele (Fig. 2)
4,11,13
. The methylated and unmethylated gDMR alleles
are recognized by different transcription factors whose function is to direct differential
epigenetic modification and imprinted expression of the locus (Fig. 2)
14
. Whereas
maternally methylated gDMRs are more numerous, intragenic and generally
correspond to promoters, often of lncRNAs, gDMRs methylated on the paternal
chromosomes are intergenic and may function as insulators or enhancers (Table
2)
1,15
. Of note, in multigenic imprinted domains, the imprinting centre often directs the
expression of genes from both the chromosome on which is methylated and the
opposite parental chromosome; this situation arises from the regulatory interactions
between imprinting centres and the gene products, both coding and noncoding,
under their control (Fig. 2).
[H2] Allele-specific expression in somatic cells
Imprinted genes can display monoallelic expression in most or all cell types, but for
some genes imprinted expression is restricted to specific tissues (for example,
UBE3A
16,17
) or developmental windows (for example, KCNQ1
18
), or monoallelic
expression and/or methylation can differ between individuals
19-21
. To control the
allele-specific expression of imprinted genes in somatic cells, gDMRs direct the
establishment of further allele-specific epigenetic features within the imprinted
domain during development. These include secondary DMRs (also known as
somatic DMRs), which correspond mostly to gene promoters and transcription factor
binding sites (Table 2)
20
, chromatin modifications and higher-order chromatin
structures (possibly resulting from CTCF–cohesin interactions)
22,23
, and lncRNAs
with silencing capacity for flanking imprinted genes in cis
24
(Figs 1, 2a) (reviewed in
REF.
1
). In other cases, imprinted gDMRs direct alternative splicing, transcription

5
elongation or polyadenylation site usage, which results in allele-specific transcript
isoforms
20,25
. A minority of genes with parent of origin-dependent expression in
somatic tissues have no evident DMR in their vicinity
20
, and their allele-specific
expression may possibly be controlled by epigenetic features other than DNA
methylation
26
.
Tandem repeats are a prominent feature of imprinting centres
27
. Some repeats
function to concentrate a high density of binding sites for transcription factors that
regulate imprinted gene expression; for example, the tandem repeats in the H19-
IGF2 IG-DMR concentrate methylation restricted binding of ZFP57 and CTCF that
are critical for imprinting (Fig. 2)
28,29
. In this case, their recombination results in
recurrent imprinting defects
30
. On the other hand, deletion of a large array of repeats
of long-interspersed elements (LINE-1) in the Dlk1–Dio3 imprinting domain in mouse
embryonic stem (ES) cells did not disrupt imprinting, or, apparently normal
development of both maternal and paternal mutant mice
31
, which does not support a
role for these repeats in imprinting.
Imprinted gene products intensify their exquisite regulation by co-operation in a
network (Imprinted gene network, IGN)
32,33
. For example, the transcription factor
PLAGL1
32
and the H19 lncRNA
33
have been shown to regulate the mRNA level of
several members of the IGN in a DNA methylation-independent manner, in mouse
tissues. The human lncRNA IPW, which resides within the Prader–Willi syndrome
(PWS) locus on chromosome 15, is able to regulate the expression of MEG3 on
chromosome 14 by targeting the EHMT2 H3K9 histone methyltransferase (also
known as G9a) to its imprinting centre
34
. Furthermore, many imprinted gene clusters
encode microRNAs (miRNAs) and small nucleolar RNAs (snoRNAs), which may be
involved in the post-transcriptional control of imprinted genes
35
. These interactions
may explain some of the overlaps observed in the phenotypes of imprinting disorders
(Table 1).
[H2] Multilocus imprinting disturbances
A subset of patients with imprinting defects exhibits multilocus imprinting
disturbances (MLID), that is, imprinting disruption at multiple loci across the genome.
MLID is confined to epimutation subgroups of imprinting disorders (Table 1) and
involves loci associated with known imprinting disorders as well as those not
currently linked with specific phenotypes
36,37
. To date, most patients with MLID have

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Abstract: DNA methylation (5-methylcytosine, 5mC) is a major form of DNA modification in the mammalian genome that plays critical roles in chromatin structure and gene expression. In general, DNA methylation is stably maintained in somatic tissues. However, DNA methylation patterns and levels show dynamic changes during development. Specifically, the genome undergoes two waves of global demethylation and remethylation for the purpose of producing the next generation. The first wave occurs in the germline, initiated with the erasure of global methylation in primordial germ cells (PGCs) and completed with the establishment of sex-specific methylation patterns during later stages of germ cell development. The second wave occurs after fertilization, including the erasure of most methylation marks inherited from the gametes and the subsequent establishment of the embryonic methylation pattern. The two waves of DNA methylation reprogramming involve both distinct and shared mechanisms. In this review article, we provide an overview of the key reprogramming events, focusing on the important players in these processes, including DNA methyltransferases (DNMTs) and ten-eleven translocation (TET) family of 5mC dioxygenases.

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Abstract: Nucleic acids are natural biopolymers of nucleotides that store, encode, transmit and express genetic information, which play central roles in diverse cellular events and diseases in living things. The analysis of nucleic acids and nucleic acids-based analysis have been widely applied in biological studies, clinical diagnosis, environmental analysis, food safety and forensic analysis. During the past decades, the field of nucleic acids analysis has been rapidly advancing with many technological breakthroughs. In this review, we focus on the methods developed for analyzing nucleic acids, nucleic acids-based analysis, device for nucleic acids analysis, and applications of nucleic acids analysis. The representative strategies for the development of new nucleic acids analysis in this field are summarized, and key advantages and possible limitations are discussed. Finally, a brief perspective on existing challenges and further research development is provided.

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Abstract: Background There is a global crisis in male reproductive health. Evidence comes from globally declining sperm counts and increasing male reproductive system abnormalities, such as cryptorchidism, germ cell tumors, and onset of puberty. Male factor infertility occurs in ~40% of couples experiencing infertility. Data demonstrate an association between male infertility and overall health. Associated significant health conditions include diabetes mellitus, metabolic disorders, and cardiovascular disease. Adding to the complexity is that men typically do not seek health care unless there is acute medical need or, as in the case of the infertile couple, the male goes for a reproductive examination and semen analysis. However, 25% of the time a reproductive health examination does not occur. Couples are increasingly utilizing IVF at more advanced ages, and advanced paternal age is associated with increased risk for (i) adverse perinatal outcomes for both offspring and mother; (ii) early child mortality, cancer, and mental health issues. In addition to age, paternal lifestyle factors, such as obesity and smoking, impact not only the male fertility but also the offspring wellness. Objectives The purpose of this paper was (i) to spotlight emerging and concerning data on male reproductive health, the relationship(s) between male reproductive and somatic health, and the heritable conditions father can pass to offspring, and (ii) to present a strategic roadmap with the goals of increasing (a) the awareness of men and society on the aforementioned, (b) the participation of men in healthcare seeking, and (c) advocacy to invigorate policy and funding agencies to support increased research into male reproductive biology. Conclusions The Male Reproductive Health Initiative (MRHI) is a newly established and rapidly growing global consortium of key opinion leaders in research, medicine, funding and policy agencies, and patient support groups that are moving forward the significant task of accomplishing the goals of the strategic roadmap.

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TL;DR: This review summarises current the authors' understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine.
Abstract: Background Human reproductive issues affecting fetal and maternal health are caused by numerous exogenous and endogenous factors, of which the latter undoubtedly include genetic changes. Pathogenic variants in either maternal or offspring DNA are associated with effects on the offspring including clinical disorders and nonviable outcomes. Conversely, both fetal and maternal factors can affect maternal health during pregnancy. Recently, it has become evident that mammalian reproduction is influenced by genomic imprinting, an epigenetic phenomenon that regulates the expression of genes according to their parent from whom they are inherited. About 1% of human genes are normally expressed from only the maternally or paternally inherited gene copy. Since numerous imprinted genes are involved in (embryonic) growth and development, disturbance of their balanced expression can adversely affect these processes. Objective and rationale This review summarises current our understanding of genomic imprinting in relation to human ontogenesis and pregnancy and its relevance for reproductive medicine. Search methods Literature databases (Pubmed, Medline) were thoroughly searched for the role of imprinting in human reproductive failure. In particular, the terms 'multilocus imprinting disturbances, SCMC, NLRP/NALP, imprinting and reproduction' were used in various combinations. Outcomes A range of molecular changes to specific groups of imprinted genes are associated with imprinting disorders, i.e. syndromes with recognisable clinical features including distinctive prenatal features. Whereas the majority of affected individuals exhibit alterations at single imprinted loci, some have multi-locus imprinting disturbances (MLID) with less predictable clinical features. Imprinting disturbances are also seen in some nonviable pregnancy outcomes, such as (recurrent) hydatidiform moles, which can therefore be regarded as a severe form of imprinting disorders. There is growing evidence that MLID can be caused by variants in the maternal genome altering the imprinting status of the oocyte and the embryo, i.e. maternal effect mutations. Pregnancies of women carrying maternal affect mutations can have different courses, ranging from miscarriages to birth of children with clinical features of various imprinting disorders. Wider implications Increasing understanding of imprinting disturbances and their clinical consequences have significant impacts on diagnostics, counselling and management in the context of human reproduction. Defining criteria for identifying pregnancies complicated by imprinting disorders facilitates early diagnosis and personalised management of both the mother and offspring. Identifying the molecular lesions underlying imprinting disturbances (e.g. maternal effect mutations) allows targeted counselling of the family and focused medical care in further pregnancies.

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Abstract: The paternal and maternal genomes are not equivalent and both are required for mammalian development. The difference between the parental genomes is believed to be due to gamete-specific differential modification, a process known as genomic imprinting. The study of transgene methylation has shown that methylation patterns can be inherited in a parent-of-origin-specific manner, suggesting that DNA methylation may play a role in genomic imprinting. The functional significance of DNA methylation in genomic imprinting was strengthened by the recent finding that CpG islands (or sites) in three imprinted genes, H19, insulin-like growth factor 2 (Igf-2), and Igf-2 receptor (Igf-2r), are differentially methylated depending on their parental origin. We have examined the expression of these three imprinted genes in mutant mice that are deficient in DNA methyltransferase activity. We report here that expression of all three genes was affected in mutant embryos: the normally silent paternal allele of the H19 gene was activated, whereas the normally active paternal allele of the Igf-2 gene and the active maternal allele of the Igf-2r gene were repressed. Our results demonstrate that a normal level of DNA methylation is required for controlling differential expression of the paternal and maternal alleles of imprinted genes.

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