Monk et al. (2019) — Genomic Imprinting Disorders

Bibliographic Reference (APA 7.0)

Monk, D., Mackay, D. J. G., Eggermann, T., Maher, E. R., & Riccio, A. (2019). Genomic imprinting disorders: Lessons on how genome, epigenome and environment interact. Nature Reviews Genetics, 20(4), 235–248. https://doi.org/10.1038/s41576-018-0092-0

Core Argument

This is a comprehensive narrative review that examines how disruption of the genomic imprinting life cycle — establishment in germ cells, maintenance through early embryonic reprogramming, and erasure in primordial germ cells — causes imprinting disorders. The authors argue that imprinting disorders arise from an interplay of three classes of causes: (1) genetic changes (pathogenic sequence variants, copy number variants, uniparental disomy), (2) epigenetic errors (primary epimutations with no detectable genetic cause and secondary epimutations driven by cis- or trans-acting mutations), and (3) environmental factors (assisted reproductive technologies, maternal nutrition, and endocrine-disrupting compounds). The review emphasizes that multilocus imprinting disturbances (MLIDs) reveal how disruption of oocyte-derived factors (notably the subcortical maternal complex, SCMC) can produce genome-wide epigenetic instability, linking imprint maintenance to broader developmental competence. The authors frame imprinting disorders as a window into the fundamental mechanisms by which the epigenome is reprogrammed across generations and maintained against environmental perturbation.

Methods

This is a narrative review synthesizing findings from human genetics studies of rare imprinting disorders, mouse models (knockout and transgenic), genome-wide methylation and chromatin studies, epidemiological surveys of ART-conceived children, and preclinical therapeutic studies. The review draws on approximately 155 primary references spanning gametogenesis, early embryogenesis, clinical genetics, and environmental epigenetics.

Key Findings

1. Molecular changes in imprinting disorders span four classes varying by disorder. The relative frequency of pathogenic gene sequence variants, copy number variants, uniparental disomy (UPD), and epimutations differs markedly between imprinting disorders, with the highest frequency of epimutations found in the chromosome 11p15-associated disorders Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). Primary epimutations occur without detectable DNA sequence changes, while secondary epimutations arise downstream from genetic changes affecting cis-acting elements or trans-acting factors.

2. MLIDs reveal that epigenetic instability can be genome-wide. A subset of individuals with imprinting defects exhibit multilocus imprinting disturbances — methylation anomalies at imprinted DMRs beyond the locus normally associated with their clinical diagnosis. MLIDs are confined to epimutation subgroups of imprinting disorders and are particularly associated with maternal-effect variants in SCMC genes (NLRP2, NLRP5, NLRP7, PADI6, OOEP). The authors propose that “MLID may be no more or less than evidence of embryonic crises during the critical window encompassing epigenetic reprogramming and ZGA, with an ascertainment bias for live birth and normal ploidy.”

3. Maternal-effect variants link DNA methylation, genome integrity, and developmental competence. Women with biallelic-inactivating NLRP7 mutations are affected by familial hydatidiform mole, in which nonviable products of conception have normal biparental genomic constitution but complete loss of maternal imprinting marks. Mouse models show that maternal ablation of SCMC gene function compromises embryonic development with disruption of genome integrity, euploidy, mitochondrial function, and gene transcription. The effects suggest a mechanistic coupling between imprint maintenance and broader genomic integrity in the early embryo.

4. Environmental factors interact with genetic susceptibility to perturb imprinting. ART procedures (ovarian hyperstimulation, IVF, ICSI, embryo culture) are associated with a ~10-fold increased risk of BWS, though the absolute risk remains <0.1% of all ART-conceived children. Maternal nutritional status — including methyl-donor availability, folate levels, and one-carbon metabolism variants — affects imprinted methylation at the 11p15.5 cluster. Prenatal exposure to the endocrine disruptor bisphenol A (BPA) alters methylation at imprinted loci including MEST and is linked to early childhood obesity. The rarity of ART-associated imprinting disorders suggests they arise from combinations of ART protocols, infertility, genetic susceptibility, and stochastic effects.

5. Therapeutic reversal of imprinting errors is emerging in preclinical models. Three therapeutic approaches have been demonstrated in mouse models of Angelman syndrome (AS) and Prader-Willi syndrome (PWS): topoisomerase inhibitors that downregulate Ube3a-ATS and reactivate paternal UBE3A, antisense oligonucleotides targeting the same antisense transcript, and G9A inhibitors that unsilence maternal snoRNAs in PWS. An additional experimental approach uses dCas9-DNMT fusion proteins to target methylation to imprinting centres, though allelic specificity remains an unsolved challenge.

Concepts Introduced or Used

• Genomic imprinting: parent-of-origin-dependent monoallelic expression driven by differential DNA methylation established during gametogenesis
• Germline differentially methylated regions (gDMRs): regions where DNA methylation differs between parental alleles in somatic cells, originating from gametes. Approximately 35 gDMRs are associated with imprinted loci in the human genome
• Imprinting centres (ICs): functional gDMRs that have been shown through genetic targeting or human mutations to regulate imprinted gene expression. Not all gDMRs qualify as imprinting centres
• Primary vs. secondary epimutations: primary epimutations occur without detectable DNA sequence change; secondary epimutations arise from genetic changes in cis-acting elements or trans-acting factors
• Multilocus imprinting disturbances (MLIDs): methylation anomalies at multiple imprinted DMRs beyond the locus associated with the clinical diagnosis
• Loss of methylation (LOM) and gain of methylation (GOM): imprinting centre methylation aberrations producing opposite clinical phenotypes (e.g., BWS and SRS are “mirror” disorders of the same 11p15.5 locus)
• Subcortical maternal complex (SCMC): a multiprotein complex (NLRP5, OOEP, TLE6, PADI6, KHDC3L) localizing to the outermost cytoplasm in oocytes, required for imprint maintenance and developmental competence in the early embryo
• Maternal-effect genes: genes encoding oocyte-derived transcripts or proteins required for early embryonic development
• Imprinted gene network (IGN): cooperative regulation among imprinted gene products, including trans-acting lncRNAs, across different chromosomes
• Somatic mosaicism: tissues containing both cells with imprinting aberrations and cells with appropriate allelic methylation, indicating a post-zygotic aetiology
• Transient imprinting: parent-of-origin-specific methylation or expression present in pre-implantation embryos or placenta that is lost or reversed later in development
• Epigenetic reprogramming: the erasure of pre-existing epigenetic marks enabling subsequent chromatin remodelling, occurring in PGCs and again after fertilization

Entities Referenced

Imprinted loci and domains:

• Chromosome 11p15.5: telomeric domain (H19/IGF2, controlled by IC1) and centromeric domain (KCNQ1OT1/CDKN1C, controlled by IC2)
• Chromosome 15q11-q13: PWS/AS locus (SNURF: TSS DMR, UBE3A)
• Chromosome 14q32: DLK1-DIO3 domain (MEG3)
• Chromosome 7q32: MEST locus
• Chromosome 6q24: PLAGL1 (TNDM locus)
• Chromosome 20q13: GNAS locus

Protein-coding genes: IGF2, H19, KCNQ1, CDKN1C, UBE3A, PLAGL1, MEST

Non-coding genes: KCNQ1OT1 (lncRNA), H19 (lncRNA), IPW (lncRNA), MEG3 (lncRNA), UBE3A-ATS, miR-675, miR-483, SNURF

Trans-acting factors and enzymes:

• DNA methyltransferases: DNMT1, DNMT3A, DNMT3B
• Cofactor: DNMT3L
• Maintenance factor: UHRF1
• TET dioxygenases: TET1, TET2, TET3
• KRAB zinc-finger protein: ZFP57
• Chromatin factors: CTCF, TRIM28 (KAP1), G9A (EHMT2)
• Histone demethylases: KDM1A (LSD1), KDM1B (LSD2)
• Transcription factors: POU5F1 (OCT4), SOX2
• Protection factor: DPPA3 (STELLA/PGC7)
• Energy sensor: SIRT1

SCMC components: NLRP2, NLRP5, NLRP7, PADI6, OOEP, TLE6, KHDC3L

Imprinting disorders:

• Beckwith-Wiedemann syndrome (BWS) — 11p15.5
• Silver-Russell syndrome (SRS) — 11p15.5 (mirror disorder of BWS)
• Prader-Willi syndrome (PWS) — 15q11-q13
• Angelman syndrome (AS) — 15q11-q13
• Transient neonatal diabetes mellitus (TNDM) — 6q24
• Kagami-Ogata syndrome — 14q32
• Familial hydatidiform mole (FHM) — NLRP7 mutations

Environmental factors discussed: ART (IVF, ICSI, ovarian hyperstimulation, embryo culture), methyl-donor availability (folate, SAM, vitamin B12), high-fat diet/obesity, bisphenol A (BPA) and other endocrine disruptors, maternal age, delayed ovulation

Limitations (as stated by authors)

• Additional human-based studies are required to resolve key differences between human and mouse in the timing and mechanisms of epigenetic remodelling, as most mechanistic knowledge of imprint erasure and establishment derives from mouse studies.
• The causation and timing of interactions between SCMC proteins and other oocyte-specific factors with DNA methylation maintenance in the early embryo remain ill-defined, as do their relationships with zygotic genome activation (ZGA).
• Genetic variants that predispose to imprinting centre epimutations remain largely unidentified, and comprehensive sequencing efforts are needed to find lower-penetrance variants with subtle effects on imprinted methylation.
• Epidemiological surveys of ART outcomes have ascertainment bias for live-born offspring with clinically blatant phenotypes; the frequency of clinical pregnancy (well known to be limited with ART) is not considered, and a definitive study requires consideration of both the epigenome and genome integrity of nonviable products of conception at all stages.
• Omic and functional analyses of early embryos and nonviable reproductive outcomes are needed to clarify the relationship between epigenomic and genomic integrity.
• Whether approaches using small molecules can revert epimutations in imprinting disorders beyond AS and PWS, and whether they can be applied in other human diseases arising from disruption of the epigenome, remains to be demonstrated.

Relevance to Clonal Evolution

While the paper focuses on congenital imprinting disorders rather than cancer, it has several connections to somatic evolution and clonal dynamics:

Shared imprinted loci are targets of LOI in cancer. The same imprinted loci disrupted in congenital imprinting disorders — notably the 11p15.5 cluster containing IGF2/H19 and CDKN1C — are frequent targets of loss of imprinting (LOI) in cancer. IGF2 LOI leads to biallelic expression of this growth factor and is one of the most common epigenetic alterations in Wilms tumour, colorectal cancer, and other malignancies. The mechanistic framework established in this review for how imprinting centre methylation is maintained — via ZFP57, CTCF, and oocyte/zygotic factors — provides the molecular context for understanding how these same protective mechanisms fail somatically during tumour evolution.

MLIDs demonstrate that epigenetic instability can be global. The observation that maternal-effect SCMC variants cause methylation defects at multiple imprinted loci genome-wide illustrates the principle that disruption of a single trans-acting maintenance factor can produce multilocus epigenetic instability. This parallels the concept of genetic-instability in clonal evolution: just as mutations in DNA repair genes produce a mutator phenotype affecting many loci simultaneously, disruption of epigenetic maintenance machinery may produce an “epimutator” phenotype affecting multiple imprinted (and potentially non-imprinted) loci. This has somatic analogues — for example, DNMT1 or UHRF1 haploinsufficiency could theoretically produce clonal populations with heterogeneous imprinting errors.

The environment-epigenome interaction has somatic parallels. The review’s detailed documentation of how environmental factors (nutrition, BPA, ART procedures) perturb imprinting during critical developmental windows raises the question of whether analogous environmental exposures, operating over much longer timescales, influence the somatic epigenome in ways that alter clonal fitness. The energy sensor SIRT1, shown to protect imprinted methylation by regulating DNMT3L acetylation, exemplifies a molecular pathway through which metabolic state could modulate epigenetic stability in somatic tissues. If nutritional or toxic exposures can erode imprint maintenance in the germline and early embryo, it is plausible that they similarly erode maintenance in adult stem cell compartments, with consequences for clonal-evolution and cancer risk.

Somatic mosaicism as a model for clonal heterogeneity. The review discusses somatic mosaicism in imprinting disorders — tissues containing both cells with imprinting aberrations and cells with normal methylation — as evidence for post-zygotic aetiology. This mosaicism is formally analogous to clonal mosaicism in ageing tissues: a stochastic epimutation occurring in a single cell, followed by propagation through mitotic divisions, generates a clonal population with an altered epigenotype. The factors that govern whether such a clone persists, expands, or is outcompeted are the same selective dynamics studied in clonal-evolution.

Imprinting centre sequences as fragile sites. The finding that tandem repeats in imprinting centres (e.g., the H19-IGF2 intergenic DMR) can undergo recombination producing recurrent imprinting defects suggests these regions are structurally fragile. In somatic evolution, such repeat-mediated instability could provide a mechanism for stochastic LOI events that confer selective advantage to a clone, analogous to how microsatellite instability accelerates clonal evolution in MMR-deficient cancers.